Aryl fused azapolycyclic compounds

ABSTRACT

This invention is directed to compounds of the formula (I): 
                         
and their pharmaceutically acceptable salts, wherein R 1 , R 2 , and R 3  are as defined herein; intermediates for the synthesis of such compounds, pharmaceutical compositions containing such compounds; and methods of using such compounds in the treatment of neurological and psychological disorders.

This application is a continuation of application Ser. No. 09/514,002,now U.S. Pat. No. 6,605,610, filed Feb. 25, 2000, which is a CIP ofapplication Ser. No. 09/402,010, now U.S. Pat. No. 6,410,550, filed Sep.28, 1999, which is a 371 of PCT/IB98/01813, filed Nov. 13, 1998, whichclaims the benefit of provisional application 60/070,245 filed Dec. 31,1997.

BACKGROUND OF THE INVENTION

This invention relates to aryl fused azapolycyclic compounds, as definedmore specifically by formula I below. Compounds of formula I bind toneuronal nicotinic acetylcholine specific receptor sites and are usefulin modulating cholinergic function. Such compounds are useful in thetreatment of inflammatory bowel disease (including but not limited toulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritablebowel syndrome, spastic dystonia, chronic pain, acute pain, celiacsprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression,bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateralsclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia,obesity, cardiac arrythmias, gastric acid hypersecretion, ulcers,pheochromocytoma, progressive supranuclear palsy, chemical dependenciesand addictions (e.g., dependencies on, or addictions to nicotine (and/ortobacco products), alcohol, benzodiazepines, barbiturates, opioids orcocaine), headache, migraine, stroke, traumatic brain injury (TBI),obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea,tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarctdementia, age-related cognitive decline, epilepsy, including petit malabsence epilepsy, senile dementia of the Alzheimer's type (AD),Parkinson's disease (PD), attention deficit hyperactivity disorder(ADHD) and Tourette's Syndrome.

The compounds of this invention may also be used in combination with anantidepressant such as, for example, a tricyclic antidepressant or aserotonin reuptake inhibiting antidepressant (SRI), in order to treatboth the cognitive decline and depression associated with AD, PD,stroke, Huntington's chorea or traumatic brain injury (TBI); incombination with muscarinic agonists in order to stimulate both centralmuscarinic and nicotinic receptors for the treatment, for example, ofALS, cognitive dysfunction, age-related cognitive decline, AD, PD,stroke, Huntington's chorea and TBI; in combination with neurotrophicfactors such as NGF in order to maximize cholinergic enhancement for thetreatment, for example, of ALS, cognitive dysfunction, age-relatedcognitive decline, AD, PD stroke, Huntington's chorea and TBI; or incombination with agents that slow or arrest AD such as cognitionenhancers, amyloid aggregation inhibitors, secretase inhibitors, taukinase inhibitors, neuronal anti-inflammatory agents and estrogen-liketherapy.

Other compounds that bind to neuronal nicotinic receptor sites arereferred to in U.S. patent application Ser. No. 08/963,852, which wasfiled on Nov. 4, 1997. The foregoing application is owned in common withthe present application, and is incorporated herein by reference in itsentirety.

SUMMARY OF THE INVENTION

This invention relates to aryl fused azapolycyclic compounds of theformula

R¹ is hydrogen, (C₁–C₆)alkyl, unconjugated (C₃–C₆)alkenyl, benzyl,XC(═O)R¹³ or —CH₂CH₂—O—(C₁–C₄)alkyl;

-   R² and R³ are selected, independently, from hydrogen,    (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, hydroxy, nitro, amino, halo, cyano,    —SO_(q)(C₁–C₆)alkyl wherein q is zero, one or two,    (C₁–C₆)alkylamino-, [(C₁–C₆)alkyl]₂amino-, —CO₂R⁴, —CONR⁵R⁶,    —SO₂NR⁷R⁸, —C(═O)R¹³, —XC(═O)R¹³, aryl-(C₀–C₃)alkyl- or    aryl-(C₀–C₃)alkyl-O—, wherein said aryl is selected from phenyl and    naphthyl, heteroaryl-(C₀–C₃)alkyl- or heteroaryl-(C₀–C₃)alkyl-O—,    wherein said heteroaryl is selected from five to seven membered    aromatic rings containing from one to four heteroatoms selected from    oxygen, nitrogen and sulfur; X²(C₀–C₆)alkyl- and    X²(C₁–C₆)alkoxy-(C₀–C₆)alkyl-, wherein X² is absent or X² is    (C₁–C₆)alkylamino- or [(C₁–C₆)alkyl]₂amino-, and wherein the    (C₀–C₆)alkyl- or (C₁–C₆)alkoxy-(C₀–C₆)alkyl- moieties of said    X²(C₀–C₆)alkyl- or X²(C₁–C₆)alkoxy-(C₀–C₆)alkyl- contains at least    one carbon atom, and wherein from one to three of the carbon atoms    of said (C₀–C₆)alkyl- or (C₁–C₆)alkoxy-(C₀–C₆)alkoxy- moieties may    optionally be replaced by an oxygen, nitrogen or sulfur atom, with    the proviso that any two such heteroatoms must be separated by at    least two carbon atoms, and wherein any of the alkyl moieties of    said (C₀–C₆)alkyl- or (C₁–C₆)alkoxy-(C₀–C₆)alkyl- groups may be    optionally substituted with from two to seven fluorine atoms, and    wherein one of the carbon atoms of each of the alkyl moieties of    said aryl-(C₀–C₃)alkyl- and said heteroaryl-(C₀–C₃)alkyl- may    optionally be replaced by an oxygen, nitrogen or sulfur atom, and    wherein each of the foregoing aryl and heteroaryl groups may    optionally be substituted with one or more substituents, preferably    from zero to two substituents, independently selected from    (C₁–C₆)alkyl optionally substituted with from one to seven fluorine    atoms, (C₁–C₆)alkoxy optionally substituted with from two to seven    fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo),    (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, hydroxy, nitro, cyano, amino,    (C₁–C₆)alkylamino-, [(C₁–C₆)alkyl]₂amino-, —CO₂R⁴, —CONR⁵R⁶,    —SO₂NR⁷R⁸, —C(═O)R¹³ and —XC(═O)R¹³;

or R² and R³, together with the carbons to which they are attached, forma four to seven membered monocyclic, or a ten to fourteen memberedbicyclic, carbocyclic ring that can be saturated or unsaturated, whereinfrom one to three of the non-fused carbon atoms of said monocyclicrings, and from one to five of the carbon atoms of said bicyclic ringsthat are not part of the benzo ring shown in formula I, may optionallyand independently be replaced by a nitrogen, oxygen or sulfur, andwherein said monocyclic and bicyclic rings may optionally be substitutedwith one or more substituents, preferably from zero to two substituentsfor the monocyclic rings and from zero to three substituents for thebicyclic rings, that are selected, independently, from (C₀–C₆)alkyl- or(C₁–C₆)alkoxy-(C₀–C₆)alkyl-, wherein the total number of carbon atomsdoes not exceed six and wherein any of the alkyl moieties may optionallybe substituted with from one to seven fluorine atoms; nitro, oxo, cyano,halo, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, hydroxy, amino,(C₁–C₆)alkylamino-, [(C₁–C₆)alkyl]₂amino-, —CO₂R⁴, —CONR⁵R⁶, —SO₂NR⁷R⁸,—C(═O)R¹³, and —XC(═O)R¹³;

each R⁴, R⁵, R⁶, R⁷, R⁸ and R¹³ is selected, independently, fromhydrogen and (C₁–C₆) alkyl, or R⁵ and R⁶, or R⁷ and R⁸ together with thenitrogen to which they are attached, form a pyrrolidine, piperidine,morpholine, azetidine, piperazine, —N—(C₁–C₆)alkylpiperazine orthiomorpholine ring, or a thiomorpholine ring wherein the ring sulfur isreplaced with a sulfoxide or sulfone; and

each X is, independently, (C₁–C₆)alkylene;

with the proviso that: (a) at least one of R¹, R² and R³ must be theother than hydrogen, and (b) when R² and R³ are hydrogen, R¹ cannot behydrogen, (C₁–C₆)alkyl, or unconjugated (C₃–C₆)alkenyl, andpharmaceutically acceptable salts of such compounds.

Examples of possible heteroaryl groups within the definition of R² andR³ are the following: thienyl, oxazoyl, isoxazolyl, pyridyl, pyrimidyl,thiazolyl, tetrazolyl, isothiazolyl, triazolyl, imidazolyl, tetrazolyl,pyrrolyl and the following groups:

wherein one of R⁹ and R¹⁸ is hydrogen or (C₁–C₆)alkyl, and the other isa bond to the benzo ring of formula I.

Examples of compounds of this invention are compounds of the formula I,and their pharmaceutically acceptable salts, wherein R² and R³, togetherwith the benzo ring of formula I, form a bicyclic ring system selectedfrom the following:

wherein R¹⁰ and R¹⁷ are selected, independently, from hydrogen,(C₁–C₆)alkyl; and (C₁–C₆)alkoxy-(C₀–C₆)alkyl- wherein the total numberof carbon atoms does not exceed six and wherein any of the alkylmoieties may optionally be substituted with from one to seven fluorineatoms; nitro, cyano, halo, amino, (C₁–C₆)alkylamino-, [(C₁–C₆)alkyl]₂amino-, —CO₂R⁴, —CONR⁵R⁶, —SO₂NR⁷R⁸, —C(═O)R¹³, —XC(═O)R¹³,phenyl and monocyclic heteroaryl wherein said heteroaryl is defined asR² and R³ are defined in the definition of compounds of the formula Iabove;

Other embodiments of this invention relate to compounds of the formulaI, and their pharmaceutically acceptable salts, wherein R² and R³,together with the benzo ring of formula I, form a bicyclic or tricyclicring system selected from the following:

wherein R¹⁰ and R¹⁷ are defined as above, and m is zero, one or two, andwherein one of the carbon atoms of ring A can optionally be replacedwith oxygen or N(C₁–C₆)alkyl.

Other embodiments of this invention relate to compounds of the formulaI, and their pharmaceutically acceptable salts, wherein neither R² norR³ is attached to the benzo ring of formula I via an oxygen atom.

Other embodiments of this invention relate to compounds of the formulaI, and their pharmaceutically acceptable salts, wherein R² and R³ donot, together with the benzo ring of formula I, form a bicyclic ortricyclic ring system.

Other embodiments of this invention relate to compounds of the formula Iwherein one or both of R² and R³ are —C(═O)R¹³, wherein R¹³ is(C₁–C₆)alkyl. Further embodiments of this invention relate to compoundsof the formula I wherein one or both of R² and R³ are —C(═O)R¹³, whereinR¹³ is (C₁–C₆)alkyl or (C₁–C₃)alkyl optionally substituted with from oneto seven fluorine atoms. Other embodiments relate to compounds of theformula I wherein one of R² and R³ is CF₃, fluoro, cyano, (C₂–C₆)alkynylor C₂F₅.

Other further embodiments of the present invention relates to compoundsof formula I having the structure

wherein R¹ is as defined above; and R² and R³ are hydrogen, (C₁–C₆)alkyloptionally substituted with from one to seven fluorine atoms;—C(═O)(C₁–C₆)alkyl, cyano, hydroxy, nitro, amino, —O(C₁–C₆)alkyl orhalo;

with the proviso that R² and R³ can not both be hydrogen when R¹ ishydrogen, (C₁–C₆)alkyl, or unconjugated (C₃–C₆)alkenyl.

Examples of specific compounds of the formula I are the followingcompounds, which, in the instances where there is a center or centers ofasymmetry in the molecule, may comprise a racemic mixture or the singleenantiomer.

-   5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;-   6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;-   6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   6-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]-pentadeca-2(10),3,5,8-tetraene;-   6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]-pentadeca-2(10),3,5,8-tetraene;-   7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]-pentadeca-2(10),3,5,8-tetraene;-   6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]-pentadeca-2(10),3,5,8-tetraene;-   6,7-dimethyl-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   14-methyl-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;-   4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;-   4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4,5-difluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;-   10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;-   4,5-dichloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;-   4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;-   3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;-   4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-one;-   6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

and pharmaceutically acceptable salts thereof.

Other embodiments compounds of the invention include but are not limitedto:

-   6-methyl-5,7-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   5,7-dimethyl-6-oxo-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   5,7-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   6-oxo-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,9-triene;-   5,8-dimethyl-6,7-dioxo-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,9-triene;-   5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   4,5-bistrifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;    and pharmaceutically acceptable salts thereof. Other embodiments of    the invention are the hydrochloride salts of the above enumerated    compounds.

This invention also relates to compounds of the formula

wherein P is hydrogen, methyl, COOR¹⁶ wherein R¹⁶ is (C₁–C₆)alkyl,allyl, 2,2,2-trichloroethyl or (C₁–C₈)alkyl; —C(═O)NR⁵R⁶ wherein R⁵ andR⁶ are defined as in formula I above; —C(═O)H, —C(═O)(C₁–C₆)alkylwherein the alkyl moiety may optionally be substituted with from 1 to 3halo atoms, preferably with from 1 to 3 fluoro or chloro atoms; benzylor t-butoxycarbonyl (t-Boc); and R¹⁴ and R¹⁵ are selected,independently, from hydrogen, (C₁–C₆)alkyl optionally substituted withfrom one to seven fluorine atoms; —C(═O)(C₁–C₆)alkyl, cyano, hydroxy,nitro, amino, —O(C₁–C₆)alkyl or halo; with the proviso that R¹⁴ and R¹⁵can not both be hydrogen when P is hydrogen, (C₁–C₆)alkyl, orunconjugated (C₃–C₆)alkenyl. Such compounds are useful as intermediatesin the synthesis of compounds of the formula I.

The invention also relates to compounds of the formula:

wherein R² and R³ are defined above; and P′ is COOR¹⁶ wherein R¹⁶ isallyl, 2,2,2-trichloroethyl or (C₁–C₆)alkyl; —C(═O)NR⁵R⁶ wherein R⁵ andR⁶ are also as defined above; —C(═O)H, —C(═O)(C₁–C₆)alkyl wherein thealkyl moiety may optionally be substituted with from 1 to 3 halo atoms,preferably with from 1 to 3 fluoro or chloro atoms; benzyl, ort-butoxycarbonyl.

Unless otherwise indicated, the term “halo”, as used herein, includesfluoro, chloro, bromo and iodo.

Unless otherwise indicated, the term “alkyl”, as used herein, includesstraight chain moieties, and where the number of carbon atoms suffices,branched and cyclic moieties.

The term “alkoxy”, as used herein, means “—O-alkyl” or “alkyl-O—”,wherein “alkyl” is defined as above.

The term “alkylene, as used herein, means an alkyl radical having twoavailable bonding sites (i.e., -alkyl-), wherein “alkyl” is defined asabove.

Unless otherwise indicated, the term “one or more substituents”, as usedherein, refers to from one to the maximum number of substituentspossible based on the number of available bonding sites.

The term “treatment”, as used herein, refers to reversing, alleviating,inhibiting the progress of, or preventing the disorder or condition towhich such term applies, or one or more symptoms of such condition ordisorder. The term “treatment”, as used herein, refers to the act oftreating, as “treating” is defined immediately above.

The compounds of formula I may have optical centers and therefore mayoccur in different enantiomeric configurations. The invention includesall enantiomers, diastereomers, and other stereoisomers of suchcompounds of formula I, as well as racemic and other mixtures thereof.

Particularly, preferred enantiomers of the invention include:

-   (+)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;-   (+)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (+)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)benzamide;-   (+)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (+)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (+)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (+)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (+)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;-   (+)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;-   (+)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;    (+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;-   (+)-N⁴,N⁴-methyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;-   (+)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;-   (+)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;-   (+)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (+)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (+)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (+)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (+)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (+)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (+)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (+)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (+)-4-ethynyl-5-chloro-10    aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (+)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (+)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;-   (+)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (+)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),    3,5,7,9-pentaene;-   (+)-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;-   (+)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;

and pharmaceutically acceptable salts thereof.

In addition, other preferred enantiomers of the compounds of theinvention include:

-   (−)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;-   (−)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (−)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;-   (−)-6-methyl-6-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (−)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-6-ethyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;-   (−)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;-   (−)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]aoetamide;-   (−)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-3-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;-   (−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;-   (−)-N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-sulfonamide;-   (−)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;-   (−)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-3-fluoro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;-   (−)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-6-methyl-5-oxo-6,13-diazatetracyclo-[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (−)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (−)-6-methyl-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (−)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;-   (−)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;-   (−)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (−)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (−)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (−)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;-   (−)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;-   (−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;-   (−)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;-   (−)-5,8,14-triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;-   (−)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,    pentaene;

and pharmaceutically acceptable salts thereof.

The present invention also relates to all radiolabeled forms of thecompounds of the formula I. Preferred radiolabeled compounds of formulaI are those wherein the radiolabels are selected from as ³H, ¹¹C, ¹⁴C,¹⁸F, ¹²³I and ¹²⁵I. Such radiolabeled compounds are useful as researchand diagnostic tools in metabolism studies, such as pharmacokineticsstudies, etc., and in binding assays in both animals and man.

The present invention also relates to a pharmaceutical composition foruse in reducing nicotine addiction or aiding in the cessation orlessening of tobacco use in a mammal, including a human, comprising anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that is effective in reducing nicotine addiction or aidingin the cessation or lessening of tobacco use and a pharmaceuticallyacceptable carrier.

The present invention also relates to a method for reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use in amammal, including a human, comprising administering to said mammal anamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof, that is effective in reducing nicotine addiction or aidingin the cessation or lessening of tobacco use.

The present invention also relates to a method of treating a disorder orcondition selected from inflammatory bowel disease (including but notlimited to ulcerative colitis, pyoderma gangrenosum and Crohn'sdisease), irritable bowel syndrome, spastic dystonia, chronic pain,acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy, chemical dependencies and addictions (e.g., dependencies on, oraddictions to nicotine (and/or tobacco products), alcohol,benzodiazepines, barbiturates, opioids or cocaine), headache, migraine,stroke, traumatic brain injury (TBI), obsessive-compulsive disorder(OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type (AD), Parkinson's disease (PD), attentiondeficit hyperactivity disorder (ADHD) and Tourette's Syndrome in amammal, comprising administering to a mammal in need of such treatmentan amount of a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, that is effective in treating such disorder orcondition.

The present invention also relates to a pharmaceutical composition fortreating a disorder or condition selected from inflammatory boweldisease (including but not limited to ulcerative colitis, pyodermagangrenosum and Crohn's disease), irritable bowel syndrome, spasticdystonia, chronic pain, acute pain, celiac sprue, pouchitis,vasoconstriction, anxiety, panic disorder, depression, bipolar disorder,autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiacarrythmias, gastric acid hypersecretion, ulcers, pheochromocytoma,progressive supranuclear palsy, chemical dependencies and addictions(e.g., dependencies on, or addictions to nicotine (and/or tobaccoproducts), alcohol, benzodiazepines, barbiturates, opioids or cocaine),headache, migraine, stroke, traumatic brain injury (TBI),obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea,tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarctdementia, age-related cognitive decline, epilepsy, including petit malabsence epilepsy, senile dementia of the Alzheimer's type (AD),Parkinson's disease (PD), attention deficit hyperactivity disorder(ADHD) and Tourette's Syndrome in a mammal, comprising an amount of acompound of the formula I, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a method for reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use in amammal, comprising administering to said mammal an amount of a compoundcomprising an amount of a compound of the formula

wherein R¹⁹ is selected from the group consisting of hydrogen,(C₁–C₆)alkyl, or unconjugated (C₃–C₆)alkenyl, or a pharmaceuticallyacceptable salt thereof, that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.

The present invention also relates to a method for treating a disorderor condition selected from inflammatory bowel disease (including but notlimited to ulcerative colitis, pyoderma gangrenosum and Crohn'sdisease), irritable bowel syndrome, spastic dystonia, chronic pain,acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction,hypertension, bulimia, anorexia, obesity, cardiac arrythmias, gastricacid hypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy, chemical dependencies and addictions (e.g., dependencies on, oraddictions to nicotine and/or tobacco products), alcohol,benzodiazepines, barbiturates, opioids or cocaine), headache, migraine,stroke, traumatic brain injury (TBI), obsessive-compulsive disorder(OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia,dyslexia, schizophrenia, multi-infarct dementia, age-related cognitivedecline, epilepsy, including petit mal absence epilepsy, senile dementiaof the Alzheimer's type (AD), Parkinson's disease (PD), attentiondeficit hyperactivity disorder (ADHD) and Tourette's Syndrome in amammal, comprising administering to a mammal in need of such treatmentan amount of a compound of the formula

where R¹⁹ is defined above, or a pharmaceutically acceptable saltthereof, that is effective in treating such disorder or condition.

This invention also relates to the pharmaceutically acceptable acidaddition salts of the compounds of formula I. Examples ofpharmaceutically acceptable acid addition salts of the compounds offormula I are the salts of hydrochloric acid, p-toluenesulfonic acid,fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid,hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid,malic acid, di-p-toluoyl tartaric acid, and mandelic acid, as well saltsformed from other acids known to those of skill in the art to formpharmaceutically acceptable acid addition salts to basic compounds.Other possible acid addition salts are, e.g., salts containingpharmaceutically acceptable anions, such as the hydroiodide, nitrate,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, and pamoate (i.e.,1.1′-methylene-bis-(2-hydroxy-3-naphthoate) salts).

The present invention also relates to methods for the preparation of thenovel compounds of formula I. The invention is directed to a process forthe preparation of a compound of formula IA:

wherein R¹⁰ is defined above, comprising the step of reacting a compoundof formula VI:

wherein Q is a nitrogen protecting group, with a compound of formulaXXIIB:

wherein R²⁰ and R²¹ are each independently (C₁–C₆)alkyl, and wherein R¹⁰is defined above; and

(ii) removing the protecting group Q.

The nitrogen protecting group Q may be chosen from suitable groups knownto those of skill in the art including —COCF₃, —COCCl₃, —COOCH₂CCl₃,—COO(C₁–C₆)alkyl and —COOCH₂C₆H₅. These groups may be added or removedby methods described for each in T. W. Greene and G. M. Wuts, ProtectiveGroups in Organic Synthesis (John Wiley & Sons, New York, 1991).Preferably, the nitrogen protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

The invention also relates to a process for the preparation of acompound of formula IB:

wherein R¹⁰ and R¹⁷ are defined above, comprising the steps of

(i) of reacting a compound of formula VI:

wherein Q is a nitrogen protecting group, with a compound of formulaXXIIB:

wherein R²⁰ and R²¹ are each independently (C₁–C₆)alkyl, and wherein R¹⁰is defined above; and

(ii) allowing the product of step (i) to react with a compound of theformula R¹⁷Z,

wherein R¹⁷ is defined above, and Z is a leaving group, in the presenceof a base;

(iii) removing the protecting group Q.

Preferably, in this method to prepare IB the leaving group is selectedfrom the group consisting of halo, halosulfonate, mesylate and tosylate,and the base is an alkali metal hydride, hydroxide or carbonate.Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

The invention also relates to another process for the preparation of acompound of formula IB:

wherein R¹⁰ and R¹⁷ are defined above, comprising the steps of

(i) of reacting a compound of formula XXIIIA:

wherein Q is a nitrogen protecting group, with a compound of formulaXXIIB:

wherein R²⁰ and R²¹ are each independently (C₁–C₆)alkyl, and wherein R¹⁰is defined above; and

(iii) removing the protecting group Q.

Preferably, in this method to prepare IB, the protecting group Q is atrifluoroacetyl or a t-butoxycarbonyl group.

The invention is also directed to a process for preparing a compound offormula IC

wherein R¹⁰ and R¹⁷ are as defined above, comprising the steps of

(i) allowing a compound of formula VI:

wherein Q is a nitrogen protecting group, to react with a compound offormula

wherein Y is an alkali metal or alkaline earth metal cation; or acompound of formula

wherein R¹⁰ and R¹⁷ are as defined above; and

(ii) removing the protecting group Q.

The protecting group Q is preferably a trifluoroacetate group or at-butoxycarbonyl group. Preferably, step (i) is conducted in a polarsolvent, more preferably, water, THF, DMF, DMSO, a mixture of water andany of THF, DMF or DMSO. In addition, the processes to make each ofcompounds IA, IB and IC, preferably comprise the further step ofreducing the nitro groups of a compound of formula IIC:

wherein Q is a nitrogen protecting group to form a compound of formulaVI

More preferably, the reduction is conducted in the presence of hydrogengas employing a palladium catalyst. Preferably, the protecting group Qis a trifluoroacetyl or a t-butoxycarbonyl group.

The invention is also directed to a process for the preparation of acompound of formula IE:

wherein R¹⁰ is defined above, comprising the steps of

(i) reducing the nitro group of a compound of formula VIIIA

wherein Q is a nitrogen protecting group;

(ii) allowing the amino product to react with an acid chloride of theformula R¹⁰COCl or an acid anhydride of the formula (R¹⁰CO)₂O whereinR¹⁰ is (C₁–C₆)alkyl, or a compound of the formula R¹⁰C((C₁–C₆)alkoxy)₃;

(iii) removing the protecting group Q.

Preferably, in this process to prepare IE, the reduction of step (i) isconducted by hydrogenation with a palladium or platinum catalyst.Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

The invention is further related to a process for the preparation of acompound of formula IF:

wherein R¹⁰ is as defined above; comprising the steps of

(i) allowing a compound of formula XA:

wherein R¹⁰ is as defined above, and Q is a nitrogen protecting group,to react with Lawesson's reagent;

(ii) allowing the product of step (i) to react with potassiumferricyanide and sodium hydroxide;

(iii) removing the protecting group Q.

Preferably, the protecting group Q is a trifluoroacetyl or at-butoxycarbonyl group.

The invention also relates to a process for preparing compounds theformula:

wherein R² and R³ are defined above; comprising the steps of

(i) subjecting a compound of formula XIIIB:

to ozonolysis conditions;

(ii) partially reducing the resulting ozonide product of step (i) to adialdehyde or product of equivalent oxidation state;

(iii) allowing the product of step (ii) to react with anarylmethylamine; and

(iv) removing the arylmethyl group.

The ozonolysis conditions used may be any of those known to those ofskill in the art. Preferably, the ozonolysis conditions are ozone inmethanol or dichloromethane, preferably methanol. In step (ii), thereduction of the ozonolysis product or ozonide is preferably conductedby hydrogenation, e.g., in the presence of hydrogen gas and a platinumor palladium catalyst with or without carbon/charcoal. Thearylmethylamine employed in step (iii) is benzylamine,4-methoxybenzylamine or 3,4-dimethoxybenzylamine, preferablybenzylamine, and is preferably added in the presence of an acidcatalyst, preferably formic acid. The removal of the arylmethyl group instep (iv) is preferably a hydrogenolysis reaction conducted, e.g., inthe presence of hydrogen gas and a platinum or palladium catalyst withor without carbon/charcoal, and in the presence of an acid catalyst.

The invention also relates to a novel process for the preparation of acompound of formula

comprising the steps of

(i) hydrogenating a compound having the formula XXVIII or XXVIII′:

wherein R² and R³ are defined above;

(ii) cyclizing the amine-ester compound of formula XXIX

obtained from step (i) to form a lactam ring compound of formula XXX

; and

(iii) reducing the carbonyl moiety.

The preferred starting material in step (i) is the trimethylsiloxycompound. The hydrogenation of step (i) is preferably conducted with apalladium or platinum catalyst under hydrogen gas, preferably in thepresence of an acid catalyst. The lactam formation of step (ii) ispreferably performed in the presence of a base, preferably analkoxyalkalide compound in a nonaqueous protic solvent, more preferablysodium tert-butoxide in methanol. The reduction of step (iii) ispreferably performed in the presence of a borane tetrahydrofurancomplex, diborane, borane dimethysulfide complex, lithium aluminumhydride or a combination of sodium borohydride and boron trifluoride,more preferably a combination of sodium borohydride and borontrifluoride.

DETAILED DESCRIPTION OF THE INVENTION

Except where otherwise stated, R¹ through R¹⁹, m, P and P′, andstructural formula I in the reaction schemes and discussion that followare defined as above. Schemes 1–10, below, illustrate methods ofsynthesizing compounds of the formula I.

Referring to Scheme 1, the starting material of formula III is reactedwith trifluoroacetic anhydride, in the presence of pyridine, to form thecompound of formula IV. This reaction is typically conducted inmethylene chloride at a temperature from about 0° C. to about roomtemperature. Other methods of generating a trifluoroacetate protectinggroup that may be used are recognized by those of skill in the art.

The compound of formula IV is then converted into the dinitro derivativeof formula IIA by the following process. The compound of the formula IVis added to a mixture of 4 or more equivalents oftrifluoromethanesulfonic acid (CF₃SO₂OH) and 2 to 3 equivalents ofnitric acid, in a chlorinated hydrocarbon solvent such as chloroform,dichloroethane (DCE) or methylene chloride. The resulting mixture isallowed to react for about 5 to 24 hours. Both of the foregoingreactions are generally conducted at a temperature ranging from about−78° C. to about 0° C. for about 2 hours, and then allowed to warm toroom temperature for the remaining time.

Reduction of the compound of formula IIA, using methods well known tothose of skill in the art, yields the compound of formula IIB. Thisreduction can be accomplished, for example, using hydrogen and apalladium catalyst such as palladium hydroxide or palladium on carbonand running the reaction in methanol at about room temperature. Thesteps of Scheme 1 can also be performed with a nitrogen-protectinggroup, other than an a trifluoroacetyl group, that would be deemedsuitable by those of skill in the art. Other suitable nitrogenprotecting groups that can be used in the procedures describedthroughout this document include —COCF₃, —COCCl₃, —COOCH₂CCl₃,—COO(C₁–C₆)alkyl and —COOCH₂C₆H₅. These groups may be added or removedby methods described for each in T. W. Greene and G. M. Wuts, ProtectiveGroups in Organic Synthesis (John Wiley & Sons, New York, 1991).

Referring to Scheme 2, the compound of formula IIA is converted into thecorresponding compound wherein the trifluoroacetyl protecting group isreplaced by a t-Boc protecting group (VIA) by reacting it first with analkali metal or alkaline earth metal (or ammonium) hydroxide orcarbonate, and then reacting the isolated product from the foregoingreaction with di-t-butyldicarbonate. Although t-Boc is used in thisinstance, other appropriate nitrogen-protecting groups known to those ofskill in the art may be used. The reaction with the alkali or alkalineearth metal (or ammonium) hydroxide or carbonate is generally carriedout in an aqueous alcohol, dioxane or tetrahydrofuran (THF) at atemperature from about room temperature to about 70° C., preferably atabout 70° C., for about one to about 24 hours. The reaction of theisolated, unprotected amine or an acid addition salt of such amine, fromthe above reaction with di-t-butyldicarbonate is preferably carried outin a solvent such as THF, dioxane or methylene chloride at a temperaturefrom about 0° C. to about room temperature. This reaction may or may notbe conducted in the presence of a base. When the reactant is a salt ofthe amine, use of a base is preferred. The resulting compound of formulaVIA can be converted into the corresponding diamino derivative offormula VIB using the procedure described above for converting thedinitro compound of formula IIA into the corresponding diamino compoundof formula IIB, or other generally accepted nitro group reductionmethods known to those of skill in the art, e.g., zinc-, tin-, oriron-mediated reductions, etc.

The conversion of the compound of formula VIB into the desired compoundof the formula VII can be accomplished by reacting the compound offormula VIB with a compound of the formula XXIIA

wherein R¹⁰ is hydrogen, (C₁–C₆)alkyl optionally substituted with fromone to seven fluorine atoms, aryl-(C₀–C₃)alkyl wherein said aryl isselected from phenyl and naphthyl, or heteroaryl-(C₀–C₃)alkyl whereinsaid heteroaryl is selected from five to seven membered aromatic ringscontaining from one to four heteroatoms selected from oxygen, nitrogenand sulfur, and wherein each of the foregoing aryl and heteroaryl groupsmay optionally be substituted with one or more substituents, preferablyfrom zero to two substituents, independently selected from (C₁–C₆)alkyloptionally substituted with from one to seven fluorine atoms,(C₁–C₆)alkoxy optionally substituted with from one to seven fluorineatoms and cyano. The preferred solvent for this reaction is a 10:1mixture of ethanol/acetic acid. The reaction temperature can range fromabout 40° C. to about 100° C. It is preferably about 60° C. Otherappropriate solvents include acetic acid, ethanol and isopropanol.

Alternate methods of preparing compounds of the formula VII the compoundof formula VIB are described by Segelstein et al., Tetrahedron Lett.,1993, 34, 1897.

Removal of the t-Boc protecting group from the compound of formula VIIyields corresponding compound of formula IA. The protecting group can beremoved using methods well known to those of skill in the art. Forexample, the compound of formula VII can be treated with an anhydrousacid such as hydrochloric acid, hydrobromic acid, methanesulfonic acid,or trifluoroacetic acid, preferably hydrochloric acid in ethyl acetate,at a temperature from about 0° C. to about 100° C., preferably fromabout room temperature to about 70° C., for about one to 24 hours.

The compound of formula VII can be converted into the correspondingcompound of formula IB by reacting it with a compound of the formulaR¹⁷Z, wherein R¹⁷ is defined as R¹⁰ is defined above, and Z is a leavinggroup such as a halo or sulfonate (e.g., chloro, bromo, mesylate ortosylate), in the presence of a base such as an alkali metal hydride,hydroxide or carbonate, preferably potassium hydroxide, in a polarsolvent such as water, dimethylsulfoxide (DMSO), THF or DMF, preferablya mixture of DMSO and water, and then removing the protecting group asdescribed above. The reaction with R¹⁷Z is generally carried out at atemperature from about room temperature to about 100° C., preferably atabout 50° C., for about five hours.

Scheme 3 illustrates an alternate method of preparing compounds of theformula IB from the compound of formula VIA. This method is thepreferred method of making compounds of the formula IB wherein R¹⁷ is abulky group such as an aryl or heteroaryl containing group, or when R¹⁷can not be attached, as illustrated in Scheme 2, by alkylation or arylsubstitution methods. Referring to Scheme 3, the compound of formula VIAis reacted with the appropriate compound of formula R¹⁷NH₂ in a polarsolvent such as THF, DMF or DMSO, preferably THF, at a temperature fromabout room temperature to about 100° C., preferably at the refluxtemperature, for about four to eighteen hours. The resulting compound offormula XXIII is then converted into the corresponding compound of theformula XXIV by reducing the nitro group to an amino group using methodswell known to those of skill in the art. Such methods are referred toabove for the conversion of the compounds of the formula IIA into acompound of the formula IIB in Scheme 1, and exemplified in experimentalExamples 12B and 18B. Closure to the imidazole ring to form thecorresponding compound of formula XXV can then be accomplished byreacting the compound of formula XXIV from the above reaction with acompound of the formula XXIIA:

wherein R¹⁰ is defined as above, as described above for convertingcompounds of the formula VIB into those of the formula VIII.

Removal of the protecting group from the compound of formula XXV yieldsthe corresponding compound of formula IB. This can be accomplished usingmethods well known in the art, for example, as described above forforming compounds of the formula IA from the corresponding compounds ofthe formula VIII.

Scheme 4 illustrates a method of preparing compounds of the formula IC,wherein R¹⁰ and R¹⁷ are as defined above. Referring to Scheme 4, thecompound of formula VIB, or analogously formula IIB in Scheme I, isreacted with a compound of the formula

(sodium bisulfite ethane dione addition adduct) in water or anotherpolar solvent such as THF, DMF or DMSO, preferably a mixture of waterand a water miscible solvent such as THF, for about one to four hours.The reaction temperature can range from about 40° C. to about 100° C.,and is preferably at about the reflux temperature.

Alternatively, the compound of formula VIB can be reacted with acompound of the formula

(double condensation reaction) in a polar solvent such as THF, water, oracetic acid, preferably a mixture of water and THF. This reaction istypically carried out at a temperature from about 40° C. to about 100°C., preferably at the reflux temperature, for about two to four hours.The desired quinoxoline of formula IC can then be formed by deprotectingthe compound formed in either of the foregoing reactions, using themethod described above for converting a compound of the formula VII intoone of the formula IA. Alternatively, in place of compound VIB in Scheme4, the compound IIB of Scheme 1 may be used analogously in thisprocedure with deprotection/reprotection as outlined in Scheme 2 (i.e.,the process of transforming IIA to VIA) in order to arrive at ultimatelythe compound IC. In general, alternative nitrogen protection groups areequally suited to the procedure of Scheme 4.

Scheme 5 illustrates a method of preparing compounds of the formula Iwherein R² and R³, together with the benzo ring to which they areattached, form a benzoxazole ring system. Such a compound, wherein R¹ ishydrogen, is depicted in Scheme 5 as chemical formula IE. Referring toScheme 5, the compound of formula XXII, wherein Y is nitro, halo,trifluoromethanesulfonate or a diazonium salt, is reacted with potassiumacetate or another alkali or alkaline earth metal carboxylate in asolvent such as dimethylsulfoxide (DMSO), DMF or acetonitrile,preferably DMSO. This reaction is generally allowed to run for about12–24 hours. Appropriate reaction temperatures range from about 70° C.to about 140° C. Approximately 100° C. is preferred.

The above reaction yields the compound of formula VIII, which can thenbe converted into the desired compound having formula IE by thefollowing procedure. First, the compound of formula VIII is reduced byreaction with hydrogen and a palladium or platinum catalyst such aspalladium hydroxide in methanol at a temperature from about 0° C. toabout 70° C., preferably at about room temperature, to form thecorresponding amino derivative. The product of this reaction is thenreacted with an acid chloride of the formula R¹⁰COCl or an acidanhydride of the formula (R¹⁰CO)₂O wherein R¹⁰ is (C₁–C₆)alkyl, or acompound of the formula R¹⁰C(OC₂H₅)₃, in an appropriate inert solventsuch as decalin, chlorobenzene or xylenes. A mixture of xylenes ispreferred. This reaction is typically conducted at a temperature fromabout 120–150° C., preferably at about 140° C. When R¹⁰COCl is used as areactant, it is preferable to add a stoichiometric amount oftriethylamine (TEA) or another organic tertiary amine base and acatalytic amount of pyridinium p-toluenesulfonic acid or pyridiniump-toluenesulfonate (PPTs) to the reaction mixture. When R¹⁰C(OC₂H₅)₃ isused as a reactant, it is preferable to add a catalytic amount of PPTsto the reaction mixture.

Removal of the trifluoroacetyl nitrogen protecting group yields thedesired compound of the formula IE. This can be accomplished usingmethods well known to those of skill in the art, for example, reactingthe protected compound with a lower alkanol and an aqueous alkali oralkaline earth metal (or ammonium) hydroxide or carbonate, aqueoussodium carbonate, at a temperature from about 50° C. to about 100° C.,preferably at about 70° C., for about two to six hours.

Scheme 6 illustrates the preparation of compounds of the formula Iwherein R¹ is hydrogen and R² and R³, together with the benzo ring towhich they are attached, form a benzothiazole ring system. Referring toScheme 6, the compound of formula III is reacted with trifluoroaceticanhydride to form the corresponding compound wherein the ring nitrogenis protected by a trifluoroacetyl group, and the resulting nitrogenprotected compound is then reacted with two equivalents oftrifluoromethanesulfonic anhydride and one equivalent of nitric acid toform the corresponding compound of formula IX, wherein there is a singlenitro substituent on the benzo ring. The reaction with trifluoroaceticacid is typically conducted in the presence of pyridine. Both of theabove reactions are typically conducted in a reaction inert solvent suchas a chlorinated hydrocarbon solvent, preferably methylene chloride, ata temperature from about 0° C. to about room temperature, preferably atabout room temperature.

The above transformation can also be accomplished using other nitrationmethods known to those skill in the art. Reduction of the nitro group toan amine group can be accomplished as described above to provide acompound of the formula IX′.

The compound of formula IX′ is then reacted with a carboxylic acidhalide or anhydride of the formula R¹⁰COX or (R¹⁰CO)₂O, wherein X ishalo and R¹⁰ is hydrogen or (C₁–C₆)alkyl, and pyridine, TEA or anothertertiary amine base, to form a compound of the formula X, which can thenbe converted to the desired compound having formula XI by reacting itwith Lawesson's reagent:

The reaction with R¹⁰COX, wherein X is halo, or (R¹⁰CO)₂O is generallycarried out at a temperature from about 0° C. to about room temperature,preferably at about room temperature. The reaction with Lawesson'sreagent is generally carried out in a reaction inert solvent such asbenzene or toluene, preferably toluene, at a temperature from about roomtemperature to about the reflux temperature of the reaction mixture,preferably at about the reflux temperature.

Closure to the benzothiazole ring and nitrogen deprotection to form thedesired compound of formula IF can be accomplished by reacting thecompound of formula XI with potassium ferricyanide and sodium hydroxidein a mixture of water and methanol (NaOH/H₂O/CH₃OH), at a temperaturefrom about 50° C. to about 70° C., preferably at about 60° C. for about1.5 hours.

Scheme 7 illustrates a method of preparing the compound of formula III,which is used as the starting material for the process of Scheme 1, or acompound of the formula IG, wherein R² and R³ form a ring (labeled “A”in the Scheme), as defined above in the definition of compounds of theformula I. Referring to Scheme 7, the compound of formula XII, whereinX¹ and X² are selected, independently, from chloro, fluoro, bromo andiodo, but where at least one of X¹ and X² is Br— or I—, reacted withcyclopentadiene, in the presence of magnesium metal, in a THF, dioxaneor other ethereal solvent, at a temperature from about 40° C. to about100° C., preferably at about the reflux temperature, to form a compoundof the formula XIII. Reaction of the resulting compound of formula XIIIwith N-methylmorpholine-N-oxide (NMO) and osmium tetroxide in acetone atabout room temperature yields the corresponding compound of the formulaXIIIA.

The compound having formula XIIIA is then converted into thecorresponding compound of formula XIV using the following procedure.First, the compound of formula XIIIA is reacted with sodium periodate ina mixture of a chlorinated hydrocarbon, preferably dichloroethane (DCE),and water, or with lead tetraacetate in a chlorinated hydrocarbonsolvent, at a temperature from about 0° C. to about room temperature, togenerate a dialdehyde or glycal intermediate. The product of thisreaction is then reacted with benzylamine and sodiumtriacetoxyborohydride in a chlorinated hydrocarbon solvent at atemperature from about 0° C. to about room temperature, preferably atabout room temperature, to form the desired compound of formula XIV.Removal of the benzyl group from the compound of formula XIV yields thecompound of formula III (when ring A is absent) or IG, (when ring A ispresent). This can be accomplished using methods well known to those ofskill in the art, for example, optionally reacting the free base withone equivalent of acid, e.g., hydrochloric acid, (to form thecorresponding acid addition salt), followed by hydrogenolysis andpalladium hydroxide in methanol at about room temperature.

In the reductive animation step described above and throughout thisdocument, alternatives to benzyl amine, such as ammonia, hydroxylamine,alkoxy amines, methyl amine, allyl amine, and substituted benzylamines(e.g., diphenylmethyl amine and 2- and 4-alkoxy substituted benzylamines) can also be used. They can be used as free bases, or as theirsalts, preferably their acetate salts, and can be subsequently removedby methods described for each in T. W. Greene and G. M. Wuts, ProtectiveGroups in Organic Synthesis (John Wiley & Sons, New York 1991).

The procedure of Scheme 7 can also be used to prepare compounds of theformula I wherein R² and R³ do not form a ring and are not bothhydrogen, by replacing the starting material of formula XII with theappropriate compound having the formula XII′

Alternatively, a compound of formula XIII can be converted, via methodsdescribed below and in Scheme 8, to compounds of formula XIV or formulaIG or formula III.

An alternative means of preparing a compound of formula III′, or asappropriate IG′, is illustrated in Scheme 7A. This process can beapplied to produce compounds of compounds of formula I, where R¹ ishydrogen, and R² and R³ are as defined above, with the exception of whenR² and R³ are hydroxy, amino, (C₁–C₆)alkylamino, ((C₁–C₆)alkyl)₂amino,—C(═O)R¹³, or —(C₁–C₆)alkylene-C(═O)R¹³.

Referring to Scheme 7A, step 1 of is an esterification of a carboxylicacid. A carboxylic acid of formula XXVI is treated with a Lewis acidcatalyst such as boron trifluoride, or with an acid catalyst such assulfuric acid, hydrochloric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, or hydrobromic acid, preferablysulfuric acid, in an alcohol solvent such as methanol, ethanol,propanol, butanol, pentanol, or hexanol, preferably methanol, at atemperature between 25 and 120° C., preferably 65° C., for a period of30 minutes to 24 hours, preferably 4 hours, to afford a compound offormula XXVIIA.

Step 2 of Scheme 7A is a cyanohydrin formation. A ketone of formulaXXVIIA is treated with a Lewis acid catalyst such as zinc iodide, zinctriflate, trimethylsilyl triflate, trimethylsilyl iodide, aluminumchloride, tin (II) chloride, or trimethyl aluminum, preferably zinciodide, or with catalytic potassium cyanide and 18-crown-6, andtrimethylsilyl cyanide, in a solvent such as acetonitrile, toluene,methylene chloride, ethyl acetate, isopropyl acetate, methyl-tert-butylether, or tetrahydrofuran, preferably a mixture of acetonitrile andtoluene, at a temperature between 0 and 100° C., preferably at 50° C.,for a period of time between 1 and 24 hours, preferably 5 hours, toafford a compound of formula XXVIIIA.

Step 3 of Scheme 7A is a hydrogenolysis reaction. A nitrile of formulaXXVIIIA is treated with an acid catalyst such as p-toluenesulfonic acid,methane sulfonic acid, hydrochloric acid, sulfuric acid, phosphoricacid, or trifluoroacetic acid, preferably p-toluenesulfonic acid, and apalladium catalyst such as palladium on carbon or palladium hydroxide oncarbon, preferably palladium hydroxide on carbon, in a solvent such asmethanol, ethanol, isopropanol, butanol, propanol, ethyl acetate,isopropyl acetate, or toluene, preferably methanol, under a hydrogenpressure of 15 to 100 psi, preferably 50 psi, for a time period between2 and 72 hours, preferably 24 hours, to afford a compound of formulaXXIXA.

Step 4 of Scheme 7A is an amide formation. An amine of formula XXIXA istreated with a base such as sodium tert-butoxide, sodium methoxide,sodium ethoxide, sodium hydroxide, potassium tert-butoxide, potassiummethoxide, potassium ethoxide, potassium hydroxide, sodium carbonate,potassium carbonate, cesium carbonate, sodium hydride, triethylamine,methylimidazole, lutidine, pyridine, methylmorpholine, ethylmorpholine,or diisopropylethylamine, preferably sodium tert-butoxide, in a solventsuch as methanol, ethanol, isopropanol, ethyl acetate, acetonitrile ortoluene, preferably methanol, at a temperature between 0 and 120° C.,preferably 65° C., for a time period between 30 minutes and 72 hours,preferably 2 hours, to afford a compound of formula XXX.

Step 5 of Scheme 7A is a reduction of an amide. An amide of formula XXXis treated with a reducing agent such as borane tetrahydrofuran complex,diborane, borane dimethylsulfide complex, lithium aluminum hydride, or acombination of sodium borohydride and boron trifluoride, preferably acombination of sodium borohydride and boron trifluoride, in a solventsuch as tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane,diisopropyl ether, 1,4-dioxane, or methyl-tert-butyl ether, preferablytetrahydrofuran, at a temperature between 0 and 80° C., preferably 50°C., for time period between 1 and 24 hours, preferably 5 hours. Theproduct is isolated by crystallization as a salt of an acid such asp-toluenesulfonic acid, methane sulfonic acid, hydrochloric acid, oxalicacid, citric acid or acetic acid, preferably p-toluenesulfonic acid, ina solvent such as isopropanol, hexane, acetone, ethyl acetate, methylethyl ketone, or toluene, preferably isopropanol, to afford the saltform of compound of formula IG or III.

Scheme 8, 9 and 10 illustrate methods of preparing compounds of theformula I wherein R¹ is hydrogen, and R² and R³ represent a variety ofdifferent substituents, as defined above, but do not form a ring.

Scheme 8 illustrates a variation of the process shown in Scheme 7, whichcan be used to make a compound identical to that of formula III exceptthat the benzo ring is substituted with a fluoro group, an alkoxy groupor any other suitable R² and/or R³ group (R¹⁸ in Scheme 8). Thiscompound is depicted in Scheme 8 as chemical structure 1H. Referring toScheme 8, where, for example, R¹⁸ is F, 1,3-difluorobenzene is reactedwith a strong base such as an alkali metal dialkylamine or an alkalimetal alkyl (or aryl) in an ethereal solvent such as ethyl ether or THF,at a temperature below −50° C., followed by quenching with iodine orN-iodosuccinamide, to form 1,3-difluoro-2-iodobenzene. The compound1,3-difluoro-2-iodobenzene (structural formula XVI in Scheme 8) is thenconverted into the compound of formula IH by a series of reactions(represented in Scheme 8 as XVI→XVII→XVIII→XIX→IH) that are analogous tothe series of reactions described above and illustrated in Scheme 7 orScheme 8A for converting compounds of the formula XIII into those of theformula IG or III. Conversion of the compound of formula XVI into thecompound of formula XVII can also be accomplished by treating a mixtureof the compound of formula XVI and cyclopentadiene with an alkyl lithiumreagent, preferably n-butyl lithium, in an inert hydrocarbon solventsuch as petroleum ether, toluene or methyl cyclohexane, at a temperaturefrom about −20° C. to about room temperature, preferably at about 0° C.This procedure is equally effective to effect the conversion as setforth in Scheme 7 with or without the R¹⁸ group present.

The compound of formula IH can then be converted into the correspondingnitrogen protected derivative of formula XX, using the methods describedabove for synthesizing the compound of formula IV in Scheme 1. Nitrationof the compound of formula XX using the method described above forpreparing the compound of formula IX in Scheme 6, yields the compound offormula XXI wherein the benzo ring is substituted with both a fluoro andnitro group, an alkoxy group and nitro group, or an R¹⁸ substituent anda nitro group. The compound of formula XXI can be used to make a varietyof compounds of the formula I wherein one of R² and R³ is fluoro, usingmethods that are well known to those of skill in the art, for example,by first converting the nitro group to an amino group, converting theamino group to a variety of other substituents, as illustrated in Scheme10, and then removing the nitrogen protecting group.

The compound of formula XXI acts as a regioisomeric functionalequivalent of the compounds having formulas IIA, VIA and XXII, in thatthe fluorine atom of formula XXI reacts similarly to the nitro and Ygroups of formula IIA, VIA, and XXII, and thus can be subjected to thesame series of reactions as those described above for the latter threecompounds, providing an alternate means for preparing the products ofsuch reactions. Similarly, the alkoxy group of formula XXI (R¹⁸=alkoxy)may be converted into a hydroxyl group before or after introduction ofthe nitro group, and then converted to isomeric products as describedabove. Also, the trifluoromethanesulfonate ester of such hydroxyderivative can act as a Y-group as described.

Preparation of compounds of formula I where R²=—O(C₁–C₆)alkyl, (C₁–C₆)alkyl or aryl wherein aryl is defined as above in the definition offormula I, and R³ is H or one of the other substituents described abovein the definition of formula I, can be prepared as described above andillustrated in Scheme 8 by replacing one of the fluorine atoms of thecompound of formula XV with —O—(C₁–C₆)alkyl, (C₁–C₆)alkyl or aryl,respectively.

Scheme 8A illustrates an alternative procedure for obtaining compoundsof formula I, where R² and R³ are as defined above, with the exceptionof (C₂–C₆)alkenyl, (C₂–C₆)alkynyl or nitro (1H′, as depicted). Step 1 ofScheme 8A is an oxidation followed by a reductive amination. Abenzonorbornadiene derivative of formula XVII′ is first treated withozone until the solution develops a blue color between 0° C. and −78°C., preferably −78° C., in a solvent such as methanol, ordichloromethane, preferably methanol. The ozonide formed is reduced byhydrogenolysis between −78° C. and room temperature, preferably between0° C. and room temperature, with platinum or palladium catalyst such asplatinum oxide, platinum on carbon, palladium on carbon, or palladiumhydroxide on carbon, preferably 5% platinum on carbon, for a period oftime between 5 minutes and 6 hours, preferably 1 hour, under a hydrogenatmosphere between 15 and 100 psi, preferably between 30 and 50 psi.Next, an arylmethylamine, such as benzylamine, 4-methoxybenzylamine, or3,4-dimethoxybenzylamine, preferably benzylamine is added to thereaction mixture at room temperature with an acid catalyst such asformic acid, acetic acid, p-toluenesulfonic acid, oxalic acid, orhydrochloric acid, preferably formic acid, and hydrogenolysis is resumedfor a period of time between 1 and 12 hours, preferably 4 hours, at ahydrogen pressure between 15 and 100 psi, preferably 50 psi, to afford acompound of formula XIX′, where Ar is an aryl group.

Step 2 of Scheme 8A is a hydrogenolysis reaction. A compound of formulaII is treated with an acid such as p-toluenesulfonic acid, hydrochloricacid, sulfuric acid, acetic acid, formic acid, or methane sulfonic acid,preferably p-toluenesulfonic acid, and a palladium catalyst such aspalladium hydroxide on carbon or palladium on carbon, preferablypalladium hydroxide on carbon, in a solvent such as methanol, ethanol,isopropanol, ethyl acetate, or methyl acetate, preferably methanol,under a hydrogen pressure between 15 and 100 psi, preferably 50 psi, ata temperature between room temperature and 60° C., preferably 40° C.,for a period of time between 1 and 48 hours, preferably 15 hours. Theproduct is crystallized as a salt depending on which acid catalyst isused in a solvent such as isopropanol, hexane, acetone, ethyl acetate,methyl ethyl ketone, or toluene, preferably in a mixture of isopropanoland hexane, to afford a compound of formula IH′.

Scheme 9 illustrates methods of preparing compounds of the formula Iwherein: (a) R¹ is hydrogen and R² is R⁷R⁸NO₂S—; (b) R¹ and R² are bothchloro; and (c) R¹ is hydrogen and R² is R¹³C(═O)—. These compounds arereferred to in Scheme 9, respectively, as compounds of formulas IJ, IKand IL.

Referring to Scheme 9, compounds of the formula IJ can be prepared byreacting the compound of formula IV with two or more equivalents of ahalosulfonic acid, preferably chlorosulfonic acid, at a temperature fromabout 0° C. to about room temperature. Reaction of the chlorosulfonicacid derivative so formed with an amine having the formula R⁷R⁸NH,wherein R⁷ and R⁸ are defined as above, followed by removal of thenitrogen protecting group, yields the desired compound having formulaIJ.

Compounds of the formula IK can be prepared by reacting the compound offormula IV with iodine trichloride in a chlorinated hydrocarbon solvent,followed by removal of the nitrogen protecting group. The reaction withiodine trichloride is typically carried out at a temperature from about0° C. to about room temperature, and is preferably carried out at aboutroom temperature. In a similar fashion, the analogous mono- ordi-brominated or mono- or di-iodinated compounds can be prepared byreacting the compound of IV with N-iodosuccinamide or N-bromosuccinimidein a trifluoromethanesulfonic acid solvent, followed by removal of thenitrogen protecting group as described above.

Reaction of the compound of IV with an acid halide of the formulaR¹³COCl or an acid anhydride of the formula (R¹³CO)₂O, with or without areaction inert solvent such as a chlorinated hydrocarbon solvent,preferably methylene chloride, in the presence of Lewis acid such asaluminum chloride, at a temperature from about 0° C. to about 100° C.,followed by nitrogen deprotection, yields the compound of formula IL.The reaction with the acid halide or anhydride can be carried out usingother known Lewis acids or other Friedel-Crafts acylation methods thatare known in the art.

The reactions described herein in which —NO₂, —SO₂NR⁷R⁸, —COR³, I, Br orCl are introduced on the compound of formula IV, as depicted in Scheme 9and described above, can be performed on any analogous compound whereinR² is hydrogen, (C₁–C₆)alkyl, halo, (C₁–C₆)alkoxy or —NHCONR⁷R⁸,producing compounds of the formula I wherein R² and R³ are defined as inthe definition of compounds of the formula I above.

Compounds that are identical to those of the formula IL, but whichretain the nitrogen protecting group, can be converted into thecorresponding O-acyl substituted compounds, i.e., those wherein the—C(═O)R¹³ group of formula IL is replaced with a —O—C(═O)R¹³ group,using Baeyer-Villiger processes well known to those skilled in the art.The resulting compounds can be partially hydrolyzed, as described inExample 35, to yield the corresponding hydroxy substituted compounds,and then alkylated to form the corresponding alkoxy substitutedcompounds. Also, as described in Example 36, such O-acyl substitutedcompounds can be used to prepare variably substituted benzisoxazoles.

Scheme 10 illustrates methods of making compounds of the formula Iwherein: (a) R¹ is hydrogen and R² is chloro; (b) R¹ is hydrogen and R²is cyano; (c) R¹ is hydrogen and R² is amino; and (d) R¹ is hydrogen andR² is R¹³C(═O)N(H)—. These compounds are referred to in Scheme 10,respectively, as compounds of the formula IM, IN, IP and IQ.

Compounds of formula IM can be prepared from compounds of the formulaIX′ by generation of a diazonium salt with, for instance, an alkalimetal nitrite and strong mineral acid (e.g., hydrochloric acid, sulfuricacid, hydrobromic acid) in water, followed by reaction with a copperhalide salt, such as copper (I) chloride. Nitrogen deprotection by themethods described above yields the desired compound of formula IM.Alternative methods for the generation of diazonium salts, as known andpracticed by those of skill in the art, can also be used. The foregoingreaction is generally carried out by temperatures ranging from about 0°C. to about 60° C., preferably about 60° C. for about 15 minutes to onehour.

Reaction of the diazodium salt, prepared as described above, withpotassium iodide in an aqueous medium provides the analogous iodidederivative. This reaction is generally carried out at a temperature fromabout 0° C. to about room temperature, preferably at about roomtemperature. The resulting compound, or its analogousN-tert-butylcarbonate protected form, can be used to prepare thecorresponding cyano derivative by reaction with copper (I) cyanide andsodium cyanide in DMF, N,N-dimethylpropylurea (DMPU) or DMSO, preferablyDMF, at a temperature from about 50° C. to about 180° C., preferablyabout 150° C. Nitrogen deprotection as described above provides thedesired compound of formula IM.

The above described iodide derivative can also be used to access avariety of other substituents such as aryl, acetylene and vinylsubstituents, as well as the corresponding carbonyl esters and amides,by palladium and nickel catalyzed processes known to those of skill inthe art, such as Heck, Suzuki and Stille couplings and Heckcarbonylations. These compounds and others, wherein R² is halo, alkyl,alkoxy, etc., may be similarly functionalized to generate compoundswherein R² and R³ are as defined above.

Nitrogen deprotection of the compound of formula IX′ provides thecompound of the formula IP. The compound of formula IX′ can be reactedwith a acyl group having the formula R¹³COCl or (R¹³CO)₂O using themethods described above, followed by nitrogen deprotection to providecompounds of the formula IQ. In a similar fashion, treatment of theprotected amine with a compound having the formula R¹³SO₂X, when X ischloro or bromo, followed by nitrogen deprotection, provides thecorresponding sulfonamide derivative.

As noted above, suitable amine protecting groups that can be used,alternatively, in the procedures described throughout this documentinclude —COCF₃, —COCCl₃, —COOCH₂CCl₃, —COO(C₁–C₆)alkyl and —COOCH₂C₆H₅.These groups may be removed by methods described for each in Greene etal.'s Protective Groups in Organic Chemistry, referred to above.Instances where protecting groups would be modified under the reactionconditions, such as, e.g., a —COOCH₂C₆H₅ group during nitration, stillpermit said procedures to operate as described with said modifiedprotecting group. Modifying the order of protecting group incorporationand/or methods of functional group introduction or modification may alsobe applied where appropriate.

In each of the reactions discussed above, or illustrated in Schemes1–10, above, pressure is not critical unless otherwise indicated.Pressures from about 0.5 atmospheres to about 5 atmospheres aregenerally acceptable, with ambient pressure, i.e., about 1 atmosphere,being preferred as a matter of convenience.

The compounds of the formula I and their pharmaceutically acceptablesalts (hereafter “the active compounds”) can be administered via eitherthe oral, transdermal (e.g., through the use of a patch), intranasal,sublingual, rectal, parenteral or topical routes. Transdermal and oraladministration are preferred. These compounds are, most desirably,administered in dosages ranging from about 0.01 mg up to about 1500 mgper day, preferably from about 0.1 to about 300 mg per day in single ordivided doses, although variations will necessarily occur depending uponthe weight and condition of the subject being treated and the particularroute of administration chosen. However, a dosage level that is in therange of about 0.001 mg to about 10 mg per kg of body weight per day ismost desirably employed. Variations may nevertheless occur dependingupon the weight and condition of the persons being treated and theirindividual responses to said medicament, as well as on the type ofpharmaceutical formulation chosen and the time period and intervalduring which such administration is carried out. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful side effects, provided that such largerdoses are first divided into several small doses for administrationthroughout the day.

The active compounds can be administered alone or in combination withpharmaceutically acceptable carriers or diluents by any of the severalroutes previously indicated. More particularly, the active compounds canbe administered in a wide variety of different dosage forms, e.g., theymay be combined with various pharmaceutically acceptable inert carriersin the form of tablets, capsules, transdermal patches, lozenges,troches, hard candies, powders, sprays, creams, salves, suppositories,jellies, gels, pastes, lotions, ointments, aqueous suspensions,injectable solutions, elixirs, syrups, and the like. Such carriersinclude solid diluents or fillers, sterile aqueous media and variousnon-toxic organic solvents. In addition, oral pharmaceuticalcompositions can be suitably sweetened and/or flavored. In general, theactive compounds are present in such dosage forms at concentrationlevels ranging from about 5.0% to about 70% by weight.

For oral administration, tablets containing various excipients such asmicrocrystalline cellulose, sodium citrate, calcium carbonate, dicalciumphosphate and glycine may be employed along with various disintegrantssuch as starch (preferably corn, potato or tapioca starch), alginic acidand certain complex silicates, together with granulation binders likepolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc can be used for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in gelatin capsules;preferred materials in this connection also include lactose or milksugar, as well as high molecular weight polyethylene glycols. Whenaqueous suspensions and/or elixirs are desired for oral administrationthe active ingredient may be combined with various sweetening orflavoring agents, coloring matter and, if so desired, emulsifying and/orsuspending agents, together with such diluents as water, ethanol,propylene glycol, glycerin and various combinations thereof.

For parenteral administration, a solution of an active compound ineither sesame or peanut oil or in aqueous propylene glycol can beemployed. The aqueous solutions should be suitably buffered (preferablypH greater than 8), if necessary, and the liquid diluent first renderedisotonic. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intraarticular,intramuscular and subcutaneous injection purposes. The preparation ofall these solutions under sterile conditions is readily accomplished bystandard pharmaceutical techniques well known to those skilled in theart.

It is also possible to administer the active compounds topically andthis can be done by way of creams, a patch, jellies, gels, pastes,ointments and the like, in accordance with standard pharmaceuticalpractice.

Biological Assay

The effectiveness of the active compounds in suppressing nicotinebinding to specific receptor sites is determined by the followingprocedure which is a modification of the methods of Lippiello, P. M. andFernandes, K. G. (in The Binding of L-[³ H]Nicotine To A Single Class ofHigh-Affinity Sites in Rat Brain Membranes, Molecular Pharm., 29,448–54, (1986)) and Anderson, D. J. and Arneric, S. P. (in NicotinicReceptor Binding of ³ H-Cystisine, ³ H-Nicotine and ³H-Methylcarmbamylcholine In Rat Brain, European J. Pharm., 253, 261–67(1994)).

Procedure

Male Sprague-Dawley rats (200–300 g) from Charles River were housed ingroups in hanging stainless steel wire cages and were maintained on a 12hour light/dark cycle (7 a.m.–7 p.m. light period). They receivedstandard Purina Rat Chow and water ad libitum.

The rats were killed by decapitation. Brains were removed immediatelyfollowing decapitation. Membranes were prepared from brain tissueaccording to the methods of Lippiello and Fernandez (Molec Pharmacol,29, 448–454, (1986) with some modifications. Whole brains were removed,rinsed with ice-cold buffer, and homogenized at 0° in 10 volumes ofbuffer (w/v) using a Brinkmann Polytron™, setting 6, for 30 seconds. Thebuffer consisted of 50 mM Tris HCl at a pH of 7.5 at room temperature.The homogenate was sedimented by centrifugation (10 minutes; 50,000×g; 0to 4° C. The supernatant was poured off and the membranes were gentlyresuspended with the Polytron and centrifuged again (10 minutes;50,000×g; 0 to 4° C. After the second centrifugation, the membranes wereresuspended in assay buffer at a concentration of 1.0 g/100 mL. Thecomposition of the standard assay buffer was 50 mM Tris HCl, 120 mMNaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂ and has a pH of 7.4 at roomtemperature.

Routine assays were performed in borosilicate glass test tubes. Theassay mixture typically consisted of 0.9 mg of membrane protein in afinal incubation volume of 1.0 mL. Three sets of tubes were preparedwherein the tubes in each set contained 50 μL of vehicle, blank, or testcompound solution, respectively. To each tube was added 200 μL of[³H]-nicotine in assay buffer followed by 750 μL of the membranesuspension. The final concentration of nicotine in each tube was 0.9 nM.The final concentration of cytisine in the blank was 1 μM. The vehicleconsisted of deionized water containing 30 μL of 1 N acetic acid per 50mL of water. The test compounds and cytisine were dissolved in vehicle.Assays were initiated by vortexing after addition of the membranesuspension to the tube. The samples were incubated at 0 to 4° C. in aniced shaking water bath. Incubations were terminated by rapid filtrationunder vacuum through Whatman GF/B™ glass fiber filters using a Brandel™multi-manifold tissue harvester. Following the initial filtration of theassay mixture, filters were washed two times with ice-cold assay buffer(5 m each). The filters were then placed in counting vials and mixedvigorously with 20 ml of Ready Safe™ (Beckman) before quantification ofradioactivity. Samples were counted in a LKB Wallach Rackbeta™ liquidscintillation counter at 40–50% efficiency. All determinations were intriplicate.

Calculations

Specific binding (C) to the membrane is the difference between totalbinding in the samples containing vehicle only and membrane (A) andnon-specific binding in the samples containing the membrane and cytisine(B), i.e.,Specific binding=(C)=(A)−(B).

Specific binding in the presence of the test compound (E) is thedifference between the total binding in the presence of the testcompound (D) and non-specific binding (B), i.e., (E)=(D)−(B).% Inhibition=(1−((E)/(C)) times 100.

The compounds of the invention that were tested in the above assayexhibited IC₅₀ values of less than 10 μM.

The following experimental examples illustrate, but do not limit thescope of, this invention.

EXAMPLE 1 10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7), 3,5-TRIENE A)1,4-Dihydro-1,4-methano-naphthalene

(Based wholly or in part on a) Wittig, G.; Knauss, E. Chem. Ber. 1958,91, 895. b) Muir, D. J.; Stothers, J. B. Can. J. Chem. 1993, 71, 1290.)

Magnesium turnings (36.5 g, 1.5 M) were stirred in anhydrous THF (250mL) in a dried 2 L 3 neck round bottom flask equipped with a 250 mLnon-equalizing addition funnel with a nitrogen (N₂) flow adapter,mechanical stirrer and efficient condenser equipped with a N₂ flowadapter. The flask was stirred and warmed to reflux by a removableheating mantle. 2-Fluorobromobenzene (2 g) was added followed by 1 mL of3N ethylmagnesium bromide (EtMgBr in THF). The addition funnel wascharged with a mixture of cyclopentadiene (94.4 g, 1.43 M, Prepared bythe method described in Org. Syn. Col., Vol. V, 414–418) andbromofluorobenzene (250 g, 1.43 M) which was maintained at 0° C. in aseparate flask by an ice bath, and transferred to the addition funnelvia cannula. Small portions (˜1 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After ˜15 minutes, thereaction initiated (exothermic, vapor condensation), the heating mantlewas removed and the contents of the addition funnel was added dropwiseat such rate as to maintain reflux (1.5 hours). The heating mantle wasre-applied and a reflux maintained for 1.5 hours. (TLC 100% hexanesR_(f) 0.67).

The reaction was cooled to room temperature and quenched with H₂O (500mL) and carefully with 1N HCl (200 mL, produces H₂ evolution fromunconsumed Mg). To this ˜50 mL concentrated HCl was added to dissolvesolids. Total addition/quench time ˜1 hour. Saturated aqueous sodiumchloride (NaCl) solution (300 mL) was added and product hexanesextracted until no potassium permanganate (KMnO₄) active product isremoved. (4×˜250 mL). The combined organic layer was washed withsaturated NaHCO₃ solution (250 mL), sodium bicarbonate Na₂SO₄ dried andconcentrated to an oil (˜200 g). The product was distilled at 78–83° C.at 15 mm (131 g, 64%). (An alternative work-up is described on p. 419Fieser and Fieser, Vol. I, Reagents for Organic Synthesis, Wiley, NY.,NY.; 1967).

B) 1,2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol

(Except for the work-up method and the quantity of OsO₄ used, based onVanRheenen, V.; Cha, D. Y.; Hartley, W. M. Org. Syn. 1988, 6, 342.)

In a 2 L 3 neck round bottom flask equipped with a N₂ flow adapter,mechanical stirrer was placed 1,4-dihydro-1,4-methano-naphthalene (79.5g, 560 mmol) stirred in acetone (800 mL) and H₂O (100 mL) and N-methylmorpholine N-oxide (67.5 g, 576 mmol). To this was added osmiumtetroxide (0SO₄) (15 mL of a 15 mol % t-butyl alcohol solution, 1.48mmol, 0.26 mol %) and the mixture was stirred vigorously. After 60hours, the reaction was filtered, and the white product rinsed withacetone and air dried (60.9 g). The mother liquor was concentrated to anoily solid: acetone trituration, filtration and acetone rinse provided(27.4 g, total 88.3 g, 89%). (TLC 50% ethyl acetate/hexanes R_(f) ˜0.5).M.p. 176–177.5° C.

C) 10-Benzyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

(Based on Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff,C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849; and Mazzocchi, P. H.;Stahly, B. C. J. Med. Chem. 1979, 22, 455.)

1,2,3,4-Tetrahydro-1,4-methano-naphthalene-2,3-diol (40 g, 227.3 mmol)was stirred in H₂O (1050 mL) and 1,2-dichloroethane (DCE) (420 mL) in a2 L round bottom flask under nitrogen with cool water bath (˜10° C.). Tothis sodium periodate (NaIO₄) (51 g, 239 mmol) and triethylbenzylammonium chloride (Et₃BnNCl) (50 mg) were added. The resulting mixturewas stirred for 1 hour (slight initial exotherm), then the layers wereseparated and the aqueous layer was extracted with DCE (200 mL). Theorganic layer was washed with H₂O (4×200 mL, or until no reaction tostarch iodide is observed in the aqueous wash) then dried through acotton plug. To this was added benzyl amine (25.5 g, 238.6 mmol) and themixture was stirred for 2 minutes then immediately transferred into thesodium triacetoxyborohydride NaHB(OAc)₃/DCE (see below) over 10 minutes.

In a separate 2 L round-bottomed flask under nitrogen was magneticallystirred NaHB(OAc)₃ (154 g, 0.727 mmol) in DCE (800 mL) at 0° C. (icebath). To this was added the above mixture over 10 minutes, withoutdelay after the dialdehyde and amine were mixed. The resulting orangemixture was allowed to warm to room temperature and stirred for 30–60minutes.

The reaction was quenched by addition of saturated sodium carbonate(Na₂CO₃) solution (˜300 mL) carefully at first and the mixture wasstirred for 1 hour (pH 9). The layers were separated and the aqueouslayer was extracted with CH₂Cl₂(2×300 mL). The organic layer was washedwith saturated aqueous NaCl solution (200 mL), dried through a cottonplug, then evaporated to a red oil. This was dissolved in a minimum ofEt₂O and filtered through a Silica pad (3×4 inch) eluting with 15% ethylacetate (ethyl acetate)/hexanes +1% of 37% aqueous ammonium hydroxide(NH₄OH) solution to remove baseline red color. Concentration affords alight yellow oil (48.5 g, 194.8 mmol, 85.7%). (TLC 10% ethylacetate/hexanes R_(f) 0.75). ¹H NMR (400 MHz, CDCl₃) δ 7.16 (m, 7H),6.89 (m, 2H), 3.48 (m, 2H), 3.08 (m, 2H), 2.80 (d, J=9.5 Hz, 2H), 2.42(d, J=9.5 Hz, 2H), 2.27 (m, 1H), 1.67 (d, J=10.0 Hz, 1H). APCI MS m/e250.3 [(M+1)⁺].

D) 10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

(For an alternative synthesis, see; Mazzocchi, P. H.; Stahly, B. C. J.Med. Chem. 1979, 22, 455.)

10-Benzyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (70.65 g,284 mmol) was stirred in ethyl acetate (250 mL) and treated with 3N HClethyl acetate (1.03 eq.) slowly with cooling (ice bath). The resultingprecipitate was filtered and rinsed with ethyl acetate. The solids weredissolved in methanol (250 mL) in a Parr bottle. To this was addedPd(OH)₂ (7 g of 20% wt/C) and the mixture was shaken under 50–40 psi ofH₂ for 24 hours or until done by TLC. The reaction was filtered througha Celite pad and concentrated to an oily solid. This was azeotroped withmethanol (methanol) (3 times) then triturated with acetone, treated withethyl ether (Et₂O) to precipitate product and filtered. Concentration ofthe mother liquors and a second treatment provided an off white solid(48.95 g, 251 mmol, 88%). (TLC 10% methanol/CH₂Cl₂ (NH₃) R_(f) 0.2). ¹HNMR (400 MHz, CDCl₃) δ 7.18 (m, 4H), 2.97 (m, 4H), 2.68 (d, J=12.5 Hz,2H), 2.41 (m, 1H), 1.95 (d, J=11.0 Hz, 1H). APCI MS m/e 160.2 [(M+1)⁺].

EXAMPLE 2 4-FLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A) 6-Fluoro-1,4-dihydro-1,4-methano-naphthalene

(Eisch, J. J.; Burlinson, N. E. J. Amer. Chem. Soc. 1976, 98, 753–761.Paquette, L. A.; Cottrell, D. M.; Snow, R. A. J. Amer. Chem. Soc. 1977,99, 3723–3733.)

Magnesium turnings (0.66 g, 27.2 mmol) were stirred in anhydrous THF (10mL) in a flame dried 75 mL 3 neck round bottom flask equipped with anon-equalizing addition funnel with a N₂ flow adapter, magnetic stirrerand efficient condenser equipped with a N₂ flow adapter. The flask wasstirred and warmed to reflux by a removable heating mantle.2,5-Difluorobromobenzene (0.1 g) was added followed by of 3N EtMgBr inTHF (0.1 mL). The addition funnel was charged with an intimate mixtureof cyclopentadiene (1.71 g, 25.9 mmol) and 2,5-difluorobromobenzene (5.0g, 25.9 mmol). Small portions (˜0.2 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After ˜15 minutes, thereaction initiated (exotherm, and vapor condensation) and heating wasmaintained as necessary during the addition of the contents of theaddition funnel. The reaction was then maintained at reflux for 1 hour.

The reaction was cooled to room temperature and quenched with H₂O (20mL) followed by aqueous 1N HCl solution (20 mL) to dissolve the solids.Saturated aqueous NaCl solution (30 mL) was added and product wasextracted with hexanes (4×25 mL). The combined organic layer was washedwith saturated aqueous NaHCO₃ solution (25 mL), dried (Na₂SO₄), filteredthrough a Silica plug with hexanes rinse and concentrated to an oil.Chromatography on Silica gel eluting with hexanes provided an oil (780mg, 19%). (TLC hexanes R_(f) 0.38). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (m,1H), 6.97 (d, J=8.0 Hz, 1H), 6.80 (br s, 1H), 6.78 (br s, 1H), 6.59 (m,1H), 3.87 (br s, 2H), 2.32 (d, J=7.0 Hz, 1H), 2.25 (d, J=7.0 Hz, 1H).

B) 6-Fluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol

6-Fluoro-1,4-dihydro-1,4-methano-naphthalene (680 mg, 4.22 mmol) andN-methyl morpholine N-oxide (599 mg, 4.43 mmol) were stirred in acetone(50 mL) and H₂O (5 mL). To this was added a solution of OsO₄ (0.2 mL,2.5% wt. solution in t-butyl alcohol, 0.02 mmol). After 72 hours,Florisil (5 g) and saturated aqueous NaHSO₃ solution (3 mL) were addedand stirred for 1 hour. The Florisil was filtered and the filtrateconcentrated to produce a crystalline product which was triturated withacetone and filtered (524 mg, 64%). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (dd,J=8.0,5.0 Hz, 1H), 6.90 (dd, J=8.0,2.3 Hz, 1H), 6.75 (ddd, J=8.0,8.0,2.3Hz, 1H), 3.79 (s, 2H), 3.18 (d, J=1.5 Hz, 2H), 2.22 (d, J=10.0 Hz, 1H),1.92 (dd, J=10.0,1.5 Hz, 1H). GCMS m/e 194 (M⁺).

C)10-Benzyl-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

6-Fluoro-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (524 mg,2.68 mmol) and Et₃NBnCl (10 mg) were vigorously stirred indichloroethane (15 mL) and H₂O (45 mL) then treated with sodiumperiodate (0.603 mg, 2.82 mmol). After 1.5 hours, the layers wereseparated and the aqueous layer extracted with DCE (2×20 mL). Thecombined organic layer was washed with H₂O (4×20 mL) until no reactionto starch iodide paper was observed, then with saturated aqueous NaClsolution (20 mL). The organic layer was dried through a cotton plug andtreated with benzyl amine (0.308 mL, 2.82 mmol) and stirred for 2minutes then transferred to an addition funnel. This solution was addedover ˜10 minutes to a vigorously stirred cooled (0° C.) mixture ofNaHB(OAc)₃ (1.82 g, 8.58 mmol) in DCE (50 mL). After addition wascomplete, the mixture was stirred without cooling for 2 hours. Themixture was quenched with saturated aqueous Na₂CO₃ solution (100 mL) andstirred for 1 hour, then the layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (3×30 mL). The combined organic layer waswashed with saturated aqueous NaCl solution (50 mL), dried through acotton plug and concentrated. Chromatography on Silica gel provided anoil (520 mg, 80%). (TLC 2% acetone/CH₂Cl₂ R_(f) 0.40). ¹H NMR (400 MHz,CDCl₃) δ 7.18 (m, 1H), 6.88 (m, 2H), 3.48 (s, 2H), 3.06 (m, 2H), 2.78(m, 2H), 2.41 (m, 2H), 2.27 (m, 1H), 1.69 (d, J=10.5 Hz, 1H).

D) 4-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

10-Benzyl-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(390 mg, 1.461 mmol), ammonium formate (3.04 g, 48.2 mmol) and 10%Pd(OH)₂/C (30 mg) were combined in methanol (50 mL) and brought toreflux under N₂ for 1.5 hours. Ammonium formate (1.0 g) was added andreflux continued for 0.5 hour. The reaction mixture was filtered througha Celite pad which was rinsed with methanol. The filtrate wasconcentrated. The residues were treated with saturated aqueous Na₂CO₃solution (30 mL) and product extracted with methylene chloride (CH₂Cl₂)(3×25 mL). The organic layer was washed with saturated aqueous NaClsolution (50 mL), dried through a cotton plug and concentrated. Theresidue was treated with 2N HCl methanol (5 mL) and concentrated thentaken up in minimum of methanol and saturated with Et₂O. After stirring18 h, the white crystals were collected by filtration (86 mg, 28%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.27). (data for free base) ¹H NMR (400MHz, CDCl₃) δ 7.06 (m, 1H), 6.83 (m, 2H), 2.89 (m, 4H), 2.61 (dd, J=12.0Hz, 2H), 2.37 (m, 1H), 1.87 (d, J=11.5 Hz, 1H). APCI MS m/e 178.2[(M+1)⁺]. (HCl salt) M.p. 260–262° C.

EXAMPLE 3 4-METHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

The title compound was prepared by the methods described in Examples 1and 2 starting with 2-fluoro-5-methylbromobenzene. (data for free base)¹H NMR (400 MHz, CDCl₃) δ 7.04 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.98 (d,J=7.5 Hz, 1H), 2.98–2.90 (m, 4H), 2.63 (m, 2H), 2.35 (m, 1H), 2.32 (s,3H), 1.87 (d, J=11.5 Hz, 1H). APCI MS m/e 174.2 [(M+1)⁺]. (HCl salt)M.p. 254–255° C. Anal. Calcd. for C₁₂H₁₂F₃N.HCl.1/3H₂O: C, 53.44; H,5.11; N, 5.19. Found C, 53.73; H, 4.82; N, 5.15.

EXAMPLE 44-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

(See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M.A.; Sall, D. J.; Seibel, W. L.; Reitz, T. J. J. Org. Chem. 1983, 48,2321–2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J. Med. Chem.1987, 30, 2191–2208.)

The title compound was prepared by the methods described in Examples 1and 2 starting with 2-fluoro-5-trifluoromethylbromobenzene. ¹H NMR (400MHz, CD₃OD) δ 7.71 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz,1H), 3.46 (m, 4H), 3.21 (d, J=12.5 Hz, 2H), 2.41 (m, 1H), 2.16 (d,J=11.5 Hz, 1H). APCI MS m/e 228.2 [(M+1)⁺]. (HCl salt) M.p. 244–246° C.Anal. Calcd. for C₁₂H₁₂F₃N.HCl.1/3H₂O: C, 53.44; H, 5.11; N, 5.19. FoundC, 53.77; H, 4.82; N, 5.18.

EXAMPLE 53-TRIFLUOROMETHYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

(See Grunewald, G. L.; Paradkar, V. M.; Pazhenchevsky, B.; Pleiss, M.A.; Sall, D. J.; Seibel, W. L.; Reitz, T. J. J. Org. Chem. 1983, 48,2321–2327. Grunewald, G. L.; Markovich, K. M.; Sall, D. J. J. Med. Chem.1987, 30, 2191–2208.)

The title compound was prepared by the methods described in Examples 1and 2 starting with 2-fluoro-6-trifluoromethylbromobenzene. ¹H NMR (400MHz, CD₃OD) δ 7.67–7.50 (3H), 3.65 (br s, 1H), 3.49–3.42 (m, 2H), 3.29(s, 1H), 3.28–3.16 (m, 2H), 2.42 (m, 1H), 2.18 (d, J=11.5 Hz, 1H). APCIMS m/e 228.2 [(M+1)⁺]. (HCl salt) M.p. 275–277° C. Anal. Calcd. forC₁₂H₁₂F₃N.HCl.1/3H₂O: C, 53.44; H, 5.11; N, 5.19. Found C, 53.73; H,4.83; N, 5.16.

EXAMPLE 6 3-FLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A) 2,6-Difluoroiodobenzene

(Roe, A. M.; Burton, R. A.; Willey, G. L.; Baines, M. W.; Rasmussen, A.C. J. Med. Chem. 1968, 11, 814–819. Tamborski, C.; Soloski, E. J. Org.Chem. 1966, 31, 746–749. Grunewald, G. L.; Arrington, H. S.; Bartlett,W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972–1982.)1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78°C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes,0.5 M) and THF (500 mL) under N₂. By controlling the addition rate theinternal temperature was maintained below −70° C. The total additiontime was ˜½ hour. The resulting slurry was stirred an additional ½ hour,then the dispersion was treated with a solution of iodine (126.9 g, 0.5M) in THF (300 mL) at a rate that maintained an internal temperaturebelow −70° C. After complete addition the mixture was allowed to warm toroom temperature, and was treated with H₂O (100 mL) and 10% aqueousNa₂S₂O₃ solution (100 mL) and stirred. The layers were separated and theaqueous layer extracted with hexanes (2×250 mL). The combined organiclayer was washed with 10% aqueous Na₂S₂O₃ solution (100 mL), H₂O (100mL), saturated aqueous NaCl solution (100 mL), dried (Na₂SO₄) filteredand concentrated to give a yellow oil (106.5 g). Distillation at ˜1–5 mmat ˜80° C. provided a light yellow oil (89.5 g, 75%). ¹H NMR (400 MHz,CDCl₃) δ 7.30 (m, 1H), 6.87 (m, 2H). GCMS m/e 240 (M⁺).

B) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene

A solution of 2,6-difluoroiodobenzene (5.0 g, 20.8 mmol) andcyclopentadiene (2.07 g, 31.3 mmol) was stirred at 0° C. in P. ether (70mL, 40–60° C.) under N₂ and treated with n-BuLi (8.74 mL, 2.5M inhexanes, 21.8 mmol) dropwise over 10 minutes. The reaction was quenchedafter 15 minutes by addition of aqueous 1N HCl solution and the productwas extracted with hexanes (3×50 mL). The combined organic layer waswashed with H₂O (50 mL), saturated aqueous NaCl solution (50 mL), dried(MgSO₄), filtered and evaporated. Chromatography on Silica gel providedproduct as an oil (1.5 g, 45%). (TLC hexanes R_(f) 0.55). ¹H NMR (400MHz, CDCl₃) δ 7.08 (ddd, J=7.0,1.0,0.8 Hz, 1H), 6.96 (ddd, J=8.5,8.3,7.0Hz, 1H), 6.86 (br s, 2H), 6.72 (ddd, J=8.5,8.3,0.8 Hz, 1H), 4.25 (br s,1H), 3.98 (br s, 1H), 2.36 (ddd, J=7.2,1.7,1.7 Hz, 1H), 2.30 (ddd,J=7.2,1.7,1.5 Hz, 1H). GCMS m/e 160 (M⁺).

C) 3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

The title compound was prepared by the methods described in Examples 2B,C, and D starting with 5-fluoro-1,4-dihydro-1,4-methano-naphthalene. ¹HNMR (400 MHz, CD₃OD) δ 7.36 (ddd, J=8.3,7.3,5.0 Hz, 1H), 7.21 (d, J=7.3Hz, 1H), 7.07 (t, J=8.3 Hz, 1H), 3.62 (br s, 1H), 3.42–3.30 (m, 3H),3.21 (m, 2H), 2.38 (m, 1H), 2.12 (d, J=11.5 Hz, 1H). APCI MS m/e 178.4[(M+1)⁺]. M.p. 269–271° C.

EXAMPLE 7 4-NITRO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A)1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene hydrochloride salt(12.4 g, 63.9 mmol) was stirred in CH₂Cl₂ (200 mL). This was cooled (icebath) and treated with pyridine (12.65 g, 160 mmol) followed bytrifluoroacetic anhydride (TFAA) (16.8 g, 11.3 mL, 80 mmol) from anaddition funnel over 10 minutes. After −3 hours, the solution was pouredinto 0.5N aqueous HCl (200 mL) and the layers separated. The aqueouslayer was extracted with CH₂Cl₂ (3×50 mL) and the combined organic layerwas washed with 0.5N aqueous HCl (50 mL), H₂O (2×50 mL) and saturatedaqueous NaHCO₃ solution (50 mL). This solution was dried through acotton plug, then diluted with ˜3% ethyl acetate and filtered through a2 inch Silica pad eluted with ˜3% ethyl acetate/CH₂Cl₂. Concentrationafforded a clear oil which crystallized to give white needles (15.35 g,60.2 mmol, 94%). (TLC 30% ethyl acetate/hexanes R_(f) 0.53). ¹H NMR (400MHz, CDCl₃) δ 7.18 (m, 4H), 4.29 (br d, J=12.6 Hz, 1H), 3.84 (br d,J=12.6 Hz, 1H), 3.51 (dd, J=12.6,1.5 Hz, 1H), 3.21 (br s, 1H), 3.10 (brs, 1H), 3.10 (br d, J=12.6 Hz, 1H), 2.37 (m, 1H), 1.92 (d, J=10.8 Hz,1H). GCMS m/e 255 (M⁺). M.p. 67–68° C.

B)1-(4-Nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

(Based on the method described by Coon, C. L.; Blucher, W. G.; Hill, M.E. J. Org. Chem. 1973, 25, 4243.) To a solution oftrifluoromethanesulfonic acid (2.4 ml, 13.7 mmol) in CH₂Cl₂ (10 ml)stirred at 0° C. was slowly added nitric acid (0.58 ml, 27.4 mmol)generating a white precipitate. After 10 minutes the resulting mixturewas cooled to −78° C. and treated with1-(10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.5 g, 13.7 mmol) in CH₂Cl₂ (15 ml) dropwise from an addition funnelover 5 minutes. The reaction was stirred at −78° C. for 30 minutes thenwarmed to 0° C. for 1 hour. The reaction mixture was poured into avigorously stirred ice (100 g). The layers were separated and theaqueous layer extracted with CH₂Cl₂ (3×30 ml). The organic layer wascombined and washed with H₂O (3×30 ml). The combined organic layer waswashed with saturated aqueous NaHCO₃ solution (20 mL) and H₂O (20 mL)then dried through a cotton plug and concentrated to give an orange oilthat solidified on standing (4.2 g). Chromatography yielded pure productas a crystalline solid (3.2 g, 78%). (TLC 30% ethyl acetate/hexanesR_(f) 0.23). ¹H NMR (400 MHz, CDCl₃) δ 8.12 (br d, J=8.0 Hz, 1H), 8.08(br s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 4.38 (br d, J=12.6 Hz, 1H), 3.94(br d, J=12.6 Hz, 1H), 3.59 (br d, J=12.6 Hz, 1H), 3.43–3.35 (m, 2H),3.18 (br d, J=12.6 Hz, 1H), 2.48 (m, 1H), 2.07 (d, J=10.8 Hz, 1H). GCMSm/e 300 (M⁺).

C) 4-Nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

1-(4-Nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(182 mg, 0.61 mmol) was stirred with Na₂CO₃ (160 mg, 1.21 mmol) inmethanol (3 mL) and H₂O (1 mL) at 70° C. for 18 hours. The mixture wasconcentrated, water was added and the product was extracted with CH₂Cl₂.The organic layer was extracted with 1N aqueous HCl (3×20 mL) and theacidic layer washed with CH₂Cl₂ (2×20 mL). The aqueous layer wasbasified to pH˜10 with Na₂CO₃(s) and product was extracted with CH₂Cl₂(3×30 mL). The organic layer was dried through a cotton plug andconcentrated to an oil. This was dissolved in methanol and treated with1N HCl in methanol, concentrated to solids which were recrystallizedfrom methanol/Et₂O to afford product as a white solid (73 mg, 50%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.38). ¹H NMR (400 MHz, DMSO-d₆) δ 8.21(s, 1H), 8.18 (dd, J=8.0,2.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 3.43 (brs, 2H), 3.28 (m, 2H), 3.07 (dd, J=13.0,13.0 Hz, 2H), 2.24 (m, 1H), 2.08(d, J=11.5 Hz, 1H). APCI MS m/e 205.1 [(M+1)⁺] M.p. 265–270° C.

EXAMPLE 8 4-AMINO-10-AZATRICYCLO[6.3.1.0 ^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

4-Nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (500 mg,2.08 mmol) was stirred in 1,4-dioxane (40 mL) and treated with saturatedaqueous Na₂CO₃ solution (15 mL). To this was added di-t-butyldicarbonate(1.8 g, 8.31 mmol). After stirring 18 hours the reaction was treatedwith H₂O (50 mL), extracted with CH₂Cl₂ (4×30 mL), dried through acotton plug and concentrated to provide an oil (500 mg, 91%).

This oil (500 mg, 1.64 mmol) was dissolved in methanol (30 mL), treatedwith 10% Pd/C (˜50 mg) and hydrogenated under a H₂ atmosphere (45 psi)for 1 hour. The mixture was filtered through a Celite pad andconcentrated to a clear oil (397 mg, 88%).

This oil (50 mg, 0.18 mmol) was stirred in 3N HCl in ethyl acetate (3mL) for 2 hours then concentrated to a white solid (25 mg, 56%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.38–7.10 (3H), 3.60 (br s, 2H), 3.25 (m, 2H), 2.98(m, 2H), 2.18 (m, 1H), 1.98 (d, J=11.5 Hz, 1H). APCI MS m/e 175.1[(M+1)⁺] M.p. 189–192° C.

EXAMPLE 9N¹-[10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL]-ACETAMIDEHYDROCHLORIDE A)1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

Hydrogenation of1-(4-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(2.0 g, 6.66 mmol) under a H₂ atmosphere (40 psi) and 10% Pd/C (200 mg)in methanol over 1.5 hours, filtration through Celite and concentrationaffords a yellow oil (1.7 g). (TLC 50% ethyl acetate/hexanes R_(f)0.27). ¹H NMR (400 MHz, CDCl₃) δ 6.99 (m, 1H), 6.64 (br s, 1H), 6.57 (m,1H), 4.25 (m, 1H), 3.82 (m, 1H), 3.50 (m, 1H), 3.17–3.07 (m, 3H), 2.35(m, 1H), 1.90 (d, J=10.8 Hz, 1H). GCMS m/e 270 (M⁺).

B)N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide

1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(850 mg, 3.14 mmol) was stirred in CH₂Cl₂ (5 mL) and treated withtriethyl amine (0.53 mL, 3.76 mmol) and acetyl chloride (0.23 mL, 3.2mmol) then stirred 18 hours. Standard NaHCO₃ work-up yielded an oilwhich was chromatographed to provide a clear oil (850 mg, 87%). (50%ethyl acetate/hexanes R_(f) 0.28).

C) N¹-[10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamidehydrochloride

N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide(100 mg, 0.32 mmol) was stirred with Na₂CO₃ (70 mg, 0.64 mmol) inmethanol (10 mL) and H₂O (2 mL) at 70° C. for 18 hours. The mixture wasconcentrated, water was added and the product was extracted with ethylacetate. The organic layer was extracted with 1N aqueous HCl (3×20 mL)and the acidic layer washed with ethyl acetate (2×20 mL). The aqueouslayer was basified to pH˜10 with Na₂CO₃ (s) and product was extractedwith ethyl acetate (3×20 mL). The organic layer was dried (sodiumsulfate (Na₂SO₄)) and concentrated to an oil. This material wasdissolved in methanol and treated with 3N HCl ethyl acetate (3 mL),concentrated and recrystallized from methanol/Et₂O to provide a solid(40 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.02 (br m, NH),7.65 (s, 1H), 7.55 (br s, NH), 7.38 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 3.33 (m, 4H), 2.96 (m, 2H), 2.13 (m, 1H), 2.00 (s, 3H), 1.96(d, J=10.5 Hz, 1H). APCI MS m/e 217.2 [(M+1)⁺]. M.p. 225–230° C.

EXAMPLE 106-METHYL-5-THIA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE A)N-(10-Trifluorothioacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-thioacetamide

N-(10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-acetamide(850 mg, 2.72 mmol) and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent) (1.1 g, 2.72 mmol) were combined in toluene (10 mL)and brought to reflux for 1.5 hours. After cooling the reaction wasworked up with ethyl acetate/saturated aqueous NaHCO₃ solution. Theorganic layer was dried (Na₂SO₄), filtered, concentrated andchromatographed on Silica gel to produce product (410 mg, 44%). (50%ethyl acetate/hexanes R_(f) 0.38)

B)6-Methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

The above oil,2,2,2-trifluoro-N-(10-trifluorothioacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-thioacetamide,(360 mg, 1.05 mmol) was dissolved in methanol (10 mL) and 1N NaOH (5 mL)and added to potassium ferricyanide (K₃Fe(CN)₆)(1.72 g, 5.23 mmol) inH₂O (10 mL). This mixture was warmed to 60° C. for 1.5 hours, cooled,concentrated and worked up with ethyl acetate/H₂O. This material wasstirred in dioxane (20 mL) and treated with H₂O (50 mL) and Na₂CO₃ toachieve pH 10. To this was added di-t-butyldicarbonate (436 mg, 2.0mmol) and the mixture was stirred for 18 hours. The reaction wasconcentrated, treated with H₂O and extracted with CH₂Cl₂. The productwas chromatographed (Silica 30% ethyl acetate/hexanes R_(f) 0.41) toyield an oil (100 mg).

The above product was treated with 3N HCl/ethyl acetate (3 mL) andwarmed to reflux for ˜15 minutes then concentrated to a solid which wasazeotroped with CH₂Cl₂ (two times). These solids were dissolved in aminimum amount of methanol then saturated with Et₂O and stirred. Theresulting white crystalline powder was collected by filtration (40 mg,14%).

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, NH), 7.65 (s, 1H), 7.82 (s, 1H),7.65 (br m, NH), 3.36 (m, 2H), 3.24 (m, 2H), 3.02 (m, 2H), 2.76 (s, 3H),2.23 (m, 1H), 2.06 (d, J=10.8 Hz, 1H). APCI MS m/e 231.1 [(M+1)⁺]. M.p.183–184° C.

EXAMPLE 114,5-DINITRO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE A)1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

(Based on the method described in Coon, C. L.; Blucher, W. G.; Hill, M.E. J. Org. Chem. 1973, 25, 4243. For an additional related example ofdinitration see: Tanida, H.; Ishitobi, H.; Irie, T.; Tsushima, T. J. Am.Chem. Soc. 1969, 91, 4512.)

To a solution of trifluoromethanesulfonic acid (79.8 ml, 902.1 mmol) inCH₂Cl₂ (550 ml) stirred at 0° C. was slowly added nitric acid (19.1 ml,450.9 mmol) generating a white precipitate. After 10 minutes,1-(10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(50 g, 196 mmol) in CH₂Cl₂ (300 ml) was added dropwise from an additionfunnel over 30 minutes. The reaction was stirred at 0° C. for 2.5 hoursand then stirred at room temperature for 24 hours. The reaction mixturewas poured into a vigorously stirred mixture of H₂O (500 ml) and ice(400 g). The layers were separated and the aqueous layer back extractedwith CH₂Cl₂ (3×300 ml). The organic layer was combined and washed withH₂O (3×300 ml). The combined aqueous layers were re-extracted withCH₂Cl₂ (2×100 ml). The organic layer was combined and washed withsaturated aqueous NaHCO₃ solution (200 mL) and H₂O (200 mL) then driedthrough a cotton plug and concentrated to solids. Trituration with ethylacetate/hexanes produced off white solids which were filtered and dried(52 g, 151 mmol, 77%. The mother liquor was chromatographed to give anadditional 4.0 g for a total of 56.0 g (82.8%). (TLC 50% ethylacetate/hexanes R_(f) 0.29) ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.75(s, 1H), 4.39 (br d, J=13.0 Hz, 1H), 3.98 (br d, J=13.0 Hz, 1H), 3.65(d, J=13.0 Hz, 1H), 3.49 (br s, 1H), 3.44 (br s, 1H), 3.24 (br d, J=12.6Hz, 1H), 2.53 (m, 1H), 2.14 (d, J=11.5 Hz, 1H). GCMS m/e 345 (M⁺).

B) 4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.7 g, 10.7 mmol) and Na₂CO₃ (2.3 g, 21.4 mmol) were combined inmethanol (50 mL) and H₂O (20 mL) then warmed to reflux for 18 hours. Thereaction was cooled, concentrated, treated with H₂O and extracted withCH₂Cl₂ (3×50 mL) then dried through a cotton plug. After concentration,the residue was chromatographed to provide brown solids. (1.9 g, 71%).(TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.36). ¹H NMR (400 MHz, CDCl₃) δ7.69 (s, 2H), 3.17 (br s, 2H), 3.11 (d, J=12.6 Hz, 2H), 2.53 (m, 1H),2.07 (d, J=11.0 Hz, 1H). GCMS m/e 249 (M⁺).

EXAMPLE 126-METHYL-7-PROPYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE A)4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene, (1.9g, 7.6 mmol) was stirred in 1,4-dioxane (75 mL) and treated withsaturated aqueous Na₂CO₃ solution (10 mL). To this was addeddi-t-butyldicarbonate (3.31 g, 15.2 mmol). After stirring 6 hours thereaction was treated with H₂O (50 mL) and extracted with ethyl acetate(4×25 mL), dried (Na₂SO₄), filtered, concentrated and chromatographed toprovide product (1.9 g, 71%). (TLC 30% ethyl acetate/hexanes (NH₃) R_(f)0.58). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (br s, 1H), 7.72 (br s, 1H), 4.08(m, 1H), 3.92 (m, 1H), 3.39 (br s, 1H), 3.27 (br s, 1H), 3.25 (m, 1H),3.18 (m, 1H), 2.46 (m, 1H), 2.02 (d, J=11.0 Hz, 1H).

B)4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (1.9 g, 5.44 mmol) was hydrogenated in methanolunder a H₂ atmosphere (45 psi) over 10% Pd/C (100 mg) for 1.5 hours thenfiltered through a Celite pad and concentrated to white solids (1.57 g,100%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.14).

C)6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

(For conditions, see; Segelstein, B. E.; Chenard, B. L.; Macor, J. E.;Post, R. J. Tetrahedron Lett. 1993, 34, 1897.)

4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (700 mg, 2.42 mmol) was dissolved in ethanol (10mL) and acetic acid (HOAc) (1 mL) and treated with1-ethoxyethylenemalononitrile (329 mg, 2.42 mmol). The resulting mixturewas warmed to 60° C. and stirred 18 hours. The reaction was cooled,concentrated treated with H₂O and saturated aqueous Na₂CO₃ solution andextracted with ethyl acetate (3×50 mL), then dried (Na₂SO₄). Afterfiltration and concentration, the residue was chromatographed to providebrown solids (247 mg, 36%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.28).

D)6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

(For conditions, see; Pilarski, B. Liebigs Ann. Chem. 1983, 1078.)6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester (80 mg, 0.267 mmol) was stirred in 50% aqueousNaOH solution (3 mL) and DMSO (1 mL) then treated with 1-iodopropane(0.03 mL, 0.321 mmol). This mixture was warmed to 40° C. for 2 hoursthen cooled, treated with H₂O and extracted with ethyl acetate. Theorganic layer was washed with H₂O (3 times) then dried (Na₂SO₄),filtered and concentrated to an oil (90 mg, 0.253 mmol). (TLC 5%methanol/CH₂Cl₂ (NH₃) R_(f) 0.15).

E)6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester (90 mg, 0.253 mmol) was dissolved in 3N HCl ethylacetate (5 mL) and warmed to 100° C. for ½ hour. The mixture was cooled,concentrated, slurried in ethyl acetate, and filtered to provide a whitesolid (25 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, NH), 7.91 (s,1H), 7.83 (br m, NH), 7.74 (s, 1H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m,2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H)1.85 (m, 2H), 0.97 (m, 3H). M.p. 147–150° C.

EXAMPLE 135,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE A)5,7,13-Triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

(For conditions, see; Segelstein, B. E.; Chenard, B. L.; Macor, J. E.;Post, R. J. Tetrahedron Lett. 1993, 34, 1897.)

4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (1.0 g, 3.45 mmol) was dissolved in ethanol (10mL) and HOAc (1 mL) and treated with ethoxymethylenemalononitrile (421mg, 3.45 mmol). The resulting mixture was warmed to 60° C. and stirred18 hours. The reaction was cooled, concentrated treated with H₂O andsaturated aqueous Na₂CO₃ solution and extracted with ethyl acetate (3×50mL), then dried (Na₂SO₄). After filtration and concentration, theresidue was chromatographed to provide brown solids (580 mg, 56%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.28)

B)5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

5,7,13-Triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, D₂O) δ 8.95 (s, 1H), 7.67 (s,2H), 3.45 (br s, 2H), 3.31 (d, J=12.5 Hz, 2H), 3.13 (d, J=12.5 Hz, 2H),2.30 (m, 1H), 1.99 (d, J=11.5 Hz, 1H). APCI MS m/e 200.1 [(M+1)⁺].M.p.>250° C.

EXAMPLE 147-METHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Example 12D,5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodomethane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, D₂O) δ 8.97 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 3.94(s, 3H), 3.48 (m, 2H), 3.33 (d, J=12.2 Hz, 2H), 3.14 (d, J=12.2 Hz, 2H),2.34 (m, 1H), 2.03 (d, J=11.5 Hz, 1H). APCI MS m/e 214.2 [(M+1)⁺].

EXAMPLE 156-METHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

6-Methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acidtert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (br m, NH),7.77 (br m, NH), 7.70 (s, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 3.05 (br d,J=11.0 Hz, 2H), 2.79 (s, 3H), 2.23 (m, 1H), 2.10 (d, J=10.8 Hz, 1H).GCMS m/e 213.5 (M⁺).

EXAMPLE 166,7-DIMETHYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Example 12D,6-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodomethane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, NH), 7.84 (s, 1H), 7.82 (br m, NH),7.72 (s, 1H), 3.90 (s, 3H), 3.45 (m, 2H), 3.28 (m, 2H), 3.04 (m, 2H),2.82 (s, 3H), 2.23 (m, 1H), 2.12 (d, J=11.0 Hz, 1H). APCI MS m/e 228.2[(M+1)⁺]. M.p. 225–230° C.

EXAMPLE 177-PROPYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Example 12D,5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by reactionwith iodopropane followed by deprotection as described in Example 12E.¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 9.45 (br s, NH), 7.97 (s, 1H),7.85 (s, 1H), 7.83 (br m, NH), 4.43 (m, 2H), 3.49 (m, 2H), 3.33 (m, 2H),3.08 (m, 2H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H), 1.92 (m, 2H), 0.93(m, 3H). APCI MS m/e 242.2 [(M+1)⁺]. M.p. 170–171° C. (subl.).

EXAMPLE 187-BUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE A)4-Butylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

(For conditions, see; Senskey, M. D.; Bradshaw, J. D.; Tessier, C. A.;Youngs, W. J. Tetrahedron Lett. 1995, 36, 6217.)

4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (500 mg, 1.43 mmol) and 1-butylamine (1.42 mL,14.3 mmol) were combined in THF (5 mL) and stirred 4 hours. The mixturewas diluted with ethyl acetate (50 mL) and washed with H₂O (3×30 mL)then dried (Na₂SO₄), filtered and concentrated to an oil. This oil waspassed through a Silica gel filter column to remove baseline impuritieseluting with 30% ethyl acetate/hexanes (510 mg, 1.41 mmol, 99%).

B)4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

4-Butylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (460 mg, 1.27 mmol) was treated with ammoniumformate (850 mg, 12.7 mmol) and 10% Pd(OH)₂/C (50 mg) in methanol (20mL) and brought to reflux for 1 hour then filtered through a Celite padand concentrated. The solids were treated with saturated aqueous Na₂CO₃solution, extracted with CH₂Cl₂ (3×30 mL) and dried by filtrationthrough a cotton plug to give an oil (440 mg, 100%).

C)7-Butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester

4-Butylamino-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (440 mg, 1.27 mmol) was dissolved in ethanol (20mL) and HOAc (2 mL) and treated with ethoxymethylenemalononitrile (186mg, 1.52 mmol). The resulting mixture was warmed to 60° C. and stirred18 hours. The reaction was cooled, concentrated, treated with H₂O andsaturated aqueous Na₂CO₃ solution then extracted with ethyl acetate(3×50 mL) and dried (Na₂SO₄). After filtration and concentration, theresidue was chromatographed to provide a yellow oil. (400 mg, 89%). (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.70).

D)7-Butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

7-Butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (brs, NH),9.68 (s, 1H), 7.99 (s, 1H), 7.92 (br m, NH), 7.87 (s, 1H), 4.50 (m, 2H),3.49 (m, 2H), 3.30 (m, 2H), 3.08 (m, 2H), 2.26 (m, 1H), 2.15 (d, J=11.0Hz, 1H), 1.88 (m, 2H), 1.32 (m, 2H), 0.82 (t, J=7.0 Hz, 3H). APCI MS m/e256.2 [(M+1)⁺]. M.p. 204–208° C.

EXAMPLE 197-ISOBUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and isobutylamine were converted to the titlecompound utilizing the methods described in Example 18A–D. ¹H NMR (400MHz, CDCl₃) δ 7.74 (s, 1H), 7.52 (s, 1H), 7.14 (s, 1H), 3.90 (dd,J=7.5,2.0 Hz, 2H), 3.04–2.97 (m, 4H), 2.70 (dd, J=12.8,2.3 Hz, 2H), 2.42(m, 1H), 2.19 (m, 1H), 1.98 (d, J=10.5 Hz, 1H), 0.93 (m, 6H). APCI MSm/e 256.2 [(M+1)⁺]. M.p. 147–150° C. (subl.).

EXAMPLE 206-METHYL-7-ISOBUTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE A)6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]-pentadeca2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester

4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolvedin ethanol (10 mL) and HOAc (2 mL) and treated with1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reactionproceeded as in Example 18C (18 h) and was worked up similarly toprovide product (TLC 3% methanol/CH₂Cl₂ (NH₃) R_(f) 0.57).

B)6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraenehydrochloride

6-Methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene-13-carboxylicacid tert-butyl ester was converted to the title compound by the methodsdescribed in Example 12E. APCI MS m/e 270.3 [(M+1)⁺]. M.p. 129–130° C.(subl.).

EXAMPLE 217-PHENYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Example 18A,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and aniline were converted to4-phenylamino-5-nitro-10-aza-tricyclo[6.3.1.0^(2,10).0^(4,8)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl at 75° C. for 4 hours in the coupling step. This wasthen converted to the title compound utilizing the methods described inExample 18B,C,D. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (1H), 7.78–7.57 (m,7H), 3.47–3.00 (m, 6H), 2.23 (m, 1H), 2.09 (d, J=11.5 Hz, 1H). APCI MSm/e 276.2 [(M+1)⁺]. M.p. 210–213° C.

EXAMPLE 22 6-METHYL-7-PHENYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENE HYDROCHLORIDE

Utilizing the methods described in Example 21 and Example 20,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and aniline were converted to the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (s, 1H), 7.73–7.56 (m, 5H), 7.32 (s,1H), 3.46–2.99 (m, 6H), 2.66 (s, 3H), 2.23 (m, 1H), 2.08 (d, J=11.0 Hz,1H). APCI MS m/e 290.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 237-NEOPENTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Example 18A–D,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and neopentylamine were converted to the titlecompound. t-Boc precursor GCMS m/e 369 (M⁺). (HCl salt) M.p.>250° C.

EXAMPLE 246-METHYL-7-NEOPENTYL-5,7,13-TRIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2(10),3,5,8-TETRAENEHYDROCHLORIDE

Utilizing the methods described in Examples 21 and 20,4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester and neopentylamine were converted to the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 7.31 (s, 1H), 7.27 (s, H), 7.02(br s, NH), 4.41 (t, J=13.0 Hz, 2H), 3.90 (s, 3H), 3.47–3.26 (m, 6H),2.20 (m, 1H), 2.00 (d, J=11.5 Hz, 1H), 0.90 (s, 9H). t-Boc precursorAPCI MS m/e 384.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 256,7-DIMETHYL-5,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

(Based on the following procedure: Jones, R. G.; McLaughlin, K. C. Org.Syn. 1963, 4, 824. b) Ehrlich, J., Bobert, M. T. J. Org. Chem. 1947,522.)

4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (100 mg, 0.35 mmol) was warmed to 80° C. in H₂O (5mL). To this butane 2,3-dione (0.034 mL, 0.38 mmol) was added under N₂for 2 hours. The reaction was cooled to room temperature and extractedwith ethyl acetate (3×40 ml). The combined organic layer was washed withH₂O (2×30 ml), dried (Na₂SO₄), filtered, concentrated andchromatographed on Silica gel to provide an oil (120 mg, 100%). The oilwas dissolved in 2N HCl methanol (5 mL) and warmed to reflux for 30minutes, then concentrated. Recrystallization from methanol/Et₂Oprovided a white powder (50 mg, 43%). (TLC ethyl acetate R_(f) 0.14). ¹HNMR (400 MHz, DMSO-d₆) δ 7.85 (s, 2H), 3.50 (br s, 2H), 3.32 (d, J=12.5Hz, 2H), 3.10 (d, J=12.5 Hz, 2H), 2.64 (s, 6H), 2.24 (m, 1H), 2.13 (d,J=11.0 Hz, 1H). t-Boc precursor APCI MS m/e 340.3 [(M+1)⁺].

EXAMPLE 265,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2trifluoro-ethanone

1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(3.0 g, 8.70 mmol) was hydrogenated in methanol (30 ml) under H₂ (45psi) over Pd(OH)₂ (300 mg of 20 wt %/C, 10% wt). After 2.5 hours thereaction was filtered through a Celite pad and rinsed with methanol (30ml). The solution was concentrated to a light brown oil whichcrystallized (2.42 g, 96%). (TLC 10% methanol/CH₂Cl₂ R_(f) 0.56). APCIMS m/e 286.2 [(M+1)⁺]. M.p. 129–131° C.

B)1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone

1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(500 mg, 1.75 mmol) was stirred in THF (2 ml). This mixture was treatedwith H₂O (2 mL) and glyoxal sodium bisulfite addition compound hydrate(931 mg, 3.50 mmol) then stirred at 55° C. for 2.5 hours. The reactionwas cooled to room temperature and extracted with ethyl acetate (3×40ml). The combined organic layer was washed with H₂O (2×30 ml), dried(Na₂SO₄), filtered, concentrated and chromatographed on Silica gel toprovide an off white powder (329 mg, 60%). (TLC 25% ethylacetate/hexanes R_(f) 0.40). M.p. 164–166° C.

C)5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene)-2,2,2-trifluoro-ethanone(320 mg, 1.04 mmol) was slurried in methanol (2.0 ml) and treated withNa₂CO₃ (221 mg, 2.08 mmol) in H₂O (2.0 ml). The mixture was warmed to70° C. for 2 hours, then concentrated, treated with H₂O (20 mL) andextracted with CH₂Cl₂ (3×10 ml). The organic layer was dried through acotton plug and concentrated to give a light yellow oil (183 mg, 83%)which solidified upon standing (M.p. 138–140° C.). This material wasdissolved in methanol (10 mL), treated with 3M HCl/ethyl acetate (3 ml),concentrated and azeotroped with methanol (2×20 mL) to give solids whichwere recrystallized from methanol/Et₂O to afford product as a whitesolid (208 mg, 97%). (TLC 5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.26). ¹H NMR(400 MHz, CD₃OD) δ 8.94 (s, 2H), 8.12 (s, 2H), 3.70 (m, 2H), 3.54 (d,J=12.5 Hz, 2H), 3.35 (d, J=12.5 Hz, 2H), 2.49 (m, 1H), 2.08 (d, J=11.0Hz, 1H). GCMS m/e 211 (M⁺). M.p. 225–230° C.

EXAMPLE 2714-METHYL-5,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]-HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE

5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene(207 mg, 0.98 mmol) was treated with 37% aqueous formaline solution (1mL) and formic acid (1 mL) then warmed to 80° C. for 1 hour. Thereaction was poured into water, made basic (NaOH, pH˜11) and extractedwith ethyl acetate. The organic layer was dried (Na₂SO₄), concentratedand chromatographed on Silica gel to provide a yellow solid. This wasstirred in methanol (2 mL) and treated with 3N HCl ethyl acetate (2 mL).After concentration the solids were recrystallized from methanol/Et₂O toafford product as a white solid (70 mg, 27%). (2% methanol/CH₂Cl₂ (NH₃)R_(f) 0.47). ¹H NMR (400 MHz, CDCl₃) δ 8.71 (s, 2H), 7.80 (s, 2H), 3.37(br s, 2H), 3.03 (m, 2H), 2.47 (m, 2H), 2.32 (m, 1H), 2.18 (br s, 3H),1.84 (d, J=11.0 Hz, 1H). APCI MS m/e 226.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 285-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE A)2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone

1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(900 mg, 2.61 mmol) and potassium acetate (KOAc) (2.6 g, 26.1 mmol) weredissolved in DMSO (10 mL) and warmed with stirring to 100° C. for 16hours. The mixture was cooled and diluted with H₂O (50 mL) thenextracted with 80% ethyl acetate/hexanes (6×25 mL). The organic layerwas washed with H₂O (3×20 mL), dried (Na₂SO₄), filtered and concentratedand purified by chromatography to give an oil (575 mg, 70%). (TLC 50%ethyl acetate/hexanes (NH₃) R_(f) 0.56)

B)2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone

2,2,2-Trifluoro-1-(4-hydroxy-5-nitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(575 mg, 1.82 mmol) was hydrogenated in methanol under a H₂ atmosphereat (45 psi) over 10% Pd/C (80 mg) for 1.5 hours then filtered through aCelite pad and concentrated to white solids (450 mg, 86%). (TLC 5%methanol/CH₂Cl₂ (NH₃) R_(f) 0.6). ¹H NMR (400 MHz, CD₃OD) δ 6.67–6.59(m, 2H), 4.12 (m, 1H), 3.73 (m, 1H), 3.73 (m, 1H), 3.51 (m, 1H), 3.07(m, 2H), 2.24 (m, 1H), 1.94 (d, J=10.5 Hz, 1H). GCMS m/e 286 (M⁺).

C)2,2,2-Trifluoro-1-(5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone

(Goldstein, S. W.; Dambek, P. J. J. Het. Chem. 1990, 27, 335.)

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), trimethyl orthoformate (0.19 mL, 1.73 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 18 mg, 0.07 mmol) and xylenes(10 mL) were combined under nitrogen and stirred at 135° C. for 18hours. The mixture was cooled, treated with H₂O and extracted with ethylacetate. The extracts were dried (Na₂SO₄), filtered, concentrated andpurified by chromatography to give an oil (110 mg, 71%). (TLC 20% ethylacetate/hexanes R_(f) 0.40)

D)5-Oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

2,2,2-Trifluoro-1-(5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone(110 mg, 0.37 mmol) was stirred in methanol (5 mL) and treated withNa₂CO₃ (78 mg, 0.74 mmol) in H₂O (2 mL). The stirred mixture was warmedto 80° C. for 2 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The product was extracted intoaqueous 1N HCl solution (2×40 mL) which was washed with ethyl acetatethen neutralized with saturated aqueous Na₂CO₃ solution to pH˜10. Theproduct was extracted with ethyl acetate (3×40 mL), dried (Na₂SO₄),concentrated and chromatographed on Silica gel to produce an oil. (TLC5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.19).

The oil was dissolved in methanol and treated with 3N HCl ethyl acetate(4 mL) then concentrated, stirred in a minimum of CH₂Cl₂ and saturatedwith hexanes. After 18 hours, the product was collected by filtration(55 mg, 63%). ¹H NMR (400 MHz, CD₃OD) δ 8.47 (s, 1H), 7.70 (s, 1H), 7.65(s, 1H), 3.41 (m, 2H), 3.30 (m, 2H), 3.10 (d, J=12.5 Hz, 2H), 2.47 (m,1H), 2.15 (d, J=11.0 Hz, 1H). APCI MS m/e 201.03 [(M+1)⁺].

EXAMPLE 296-METHYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE A) 2,2,2-Trifluoro-1-(6-methyl5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), triethyl orthoacetate (0.34 mL, 1.83 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol) and xylenes(10 mL) were combined under nitrogen and stirred at 135° C. for 18hours. Work-up, isolation and purification as in Example 28C providedthe title compound (90 mg, 55%).

B)6-Methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraenehydrochloride

2,2,2-Trifluoro-1-(6-methyl5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene)-ethanone(90 mg, 0.30 mmol) was stirred in methanol (5 mL) and treated withNa₂CO₃ (61 mg, 0.58 mmol) in H₂O (2 mL). The stirred mixture was warmedto 80° C. for 2 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The solution was dried (Na₂SO₄),concentrated, and chromatographed on Silica gel to produce an oil. (TLC10% methanol/CH₂Cl₂ (NH₃) R_(f) 0.18). ¹H NMR (free base) (400 MHz,CDCl₃) δ 7.40 (s, 1H), 7.26 (s, 1H), 3.05–2.98 (m, 4H), 2.72 (d, J=12.8Hz, 2H), 2.59 (s, 3H), 2.46 (m, 1H), 1.98 (d, J=10.5 Hz, 1H).

The oil was dissolved in methanol and treated with 3N HCl ethyl acetate(4 mL) then concentrated, stirred in a minimum of CH₂Cl₂ and saturatedwith hexanes. After 18 hours, the product was collected by filtration(10 mg, 13%). APCI MS m/e 215.2 [(M+1)⁺]. M.p.>250° C.

EXAMPLE 302-FLUORO-N-(4-HYDROXY-10-AZA-TRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIEN-5-YL)-BENZAMIDEHYDROCHLORIDE

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(150 mg, 0.524 mmol), 2-fluorobenzoyl chloride (0.07 mL, 0.576 mmol),pyridinium-p-toluenesulfonic acid (PPTS, 20 mg, 0.08 mmol), pyridine(0.046 mL, 0.576 mmol) and xylenes (5 mL) were combined under nitrogenand stirred at 135° C. for 18 hours. After 24 hours, additional PPTS (50mg) was added and the material stirred at 135° C. for an additional 24hours. Work-up as above provided crude product (145 mg, 0.375 mmol)which was combined with Na₂CO₃(s) (80 mg, 0.75 mmol) in methanol (5 mL)and H₂O (2 mL) and heated to reflux. After 3 hours, the reaction wascooled and diluted with water then extracted with CH₂Cl₂ (4×40 mL),dried through a cotton plug then chromatographed to remove baselineimpurity (5% methanol/CH₂Cl₂ (NH₃)). The crude material was treated withexcess 3N HCl ethyl acetate and concentrated, then dissolved in aminimum of methanol and the solution was saturated with Et₂O andstirred. After stirring 4 hours the product was collected by filtration(85 mg, 68%). ¹H NMR (400 MHz, CD₃OD) δ 7.99 (m, 2H), 7.59 (m, 1H),7.36–7.23 (m, 2H), 6.82 (s, 1H), 2.99 (m, 4H), 2.78 (m, 2H), 2.35 (m,1H), 1.96 (d, J=10.5 Hz, 1H). APCI MS m/e 313.1 [(M+1)⁺]. M.p. 125–130°C. (subl.).

EXAMPLE 31 4-CHLORO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A)1-(4-Chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

Copper(l)chloride (CuCl) was prepared as follows: CuSO₄ (4.3 g) and NaCl(1.2 g) were dissolved in hot H₂O (14 mL). sodium bisulfite (NaHSO₃) (1g) and sodium hydroxide (NaOH) (690 mg) were dissolved in H₂O (7 mL) andadded to the hot acidic solution over 5 minutes. The precipitated whitesolids were filtered and washed with water.

1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(460 mg, 1.7 mmol) was dissolved in H₂O (2 mL) and concentrated HClsolution (1 mL) then cooled to 0° C. and treated with a solution ofsodium nitrite (NaNO₂) (275 mg) in H₂O (1 mL) dropwise. To the resultingsolution was added a CuCl (202 mg, prepared as described above, 2.04mmol) in concentrated HCl solution (2 mL) over 10 minutes (gas evolutionobserved). The resulting solution was warmed to 60° C. for 15 minutes,then was cooled to room temperature and extracted with ethyl acetate(4×30 mL). After drying over Na₂SO₄, the solution was filtered andconcentrated to an oil which was filtered through a Silica pad to removebaseline material eluting with 50% ethyl acetate/hexanes to give an oil(470 mg, 95%).

B) 4-Chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

1-(4-Chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(470 mg, 1.62 mmol) and Na₂CO₃ (344 mg, 3.24 mmol) in methanol (30 mL)and H₂O (10 mL) were heated to reflux. After 2 hours, the reaction wascooled and diluted with water then extracted with ethyl acetate (4×40mL), dried (Na₂SO₄), filtered and concentrated to a yellow oil. Thecrude material was treated with excess 3N HCl ethyl acetate andconcentrated, then dissolved in a minimum of CH₂Cl₂ and the solution wassaturated with hexanes and stirred. After stirring 4 hours the productwas collected by filtration (155 mg, 42%). ¹H NMR (free base) (400 MHz,CDCl₃) δ 7.15 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 3.00–2.94 (m, 4H), 2.68,(m, 2H), 2.38 (m, 1H), 1.92 (d, J=10.5 Hz, 1H). ¹H NMR (HCl salt) (400MHz, DMSO-d₆) δ 7.30–7.20 (m, 3H), 3.30–3.15 (m, 6H), 2.37 (m, 1H), 1.89(d, J=11.0 Hz, 1H). APCI MS m/e 194.1 [(M+1)⁺].

EXAMPLE 32 10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YLCYANIDE HYDROCHLORIDE A)1-(4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(500 mg, 1.85 mmol) was dissolved in H₂O (5 mL) and concentrated H₂SO₄solution (0.5 mL) then cooled to 0° C. and treated with a solution ofsodium nitrite (NaNO₂) (140 mg, 2.04 mmol) in H₂O (2 mL) dropwise.Potassium iodide (460 mg, 2.78 mmol) in 1N H₂SO₄ solution (0.5 mL) wasadded over 10 minutes (reaction becomes dark red). The resultingsolution was warmed to room temperature and stirred 18 hours. Thereaction was quenched with NaHSO₃ and water (pH 2.5) then extracted withethyl acetate (4×30 mL). After drying (Na₂SO₄), the solution wasfiltered and concentrated to a yellow oil which was chromatographed onSilica gel to provide a yellow oil. (260 mg, 37%). (TLC 30% ethylacetate/hexanes R_(f) 0.70). (A 5.4 g scale performed as above yielded 5g, 67%).

B)4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

1-(4-Iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(5 g, 13.1 mmol) and 37% saturated aqueous NH₄OH solution (50 mL) werestirred in methanol (250 ml) for 2 hours then concentrated andazeotroped with methanol (2×50 mL). The resulting product was stirred in1,4-dioxane (75 mL) and treated with saturated Na₂CO₃ solution (15 mL).To this was added di-t-butyldicarbonate (5.71 g, 26.2 mmol). Afterstirring 18 hours the reaction was treated with H₂O (50 mL) andextracted with CH₂Cl₂ (4×30 mL), dried (Na₂SO₄), filtered, concentratedand chromatographed on Silica gel (TLC 20% ethyl acetate/hexanes) toprovide product as an oil (4.9 g, 98%).

C)4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

(Utilizing the methods described in: House, H. O.; Fischer, W. F. J.Org. Chem. 1969, 3626.)

CuCN (108 mg, 1.21 mmol) and NaCN (59 mg, 1.21 mmol) were combined indry DMF (6 mL) and warmed to 150° C. under N₂. Solution occurs in 20minutes. To this was added4-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (232 mg, 0.6 mmol) in DMF (3.5 mL) and the mixturewas stirred for 18 hours at 150° C. The reaction was cooled and dilutedwith 50% saturated aqueous NaCl solution and extracted with 50% ethylacetate/hexanes (3×30 mL). After drying (Na₂SO₄), filtration andconcentration the product was isolated by chromatography (86 mg, 50%).(TLC 20% ethyl acetate/hexanes R_(f) 0.28).

D) 10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanidehydrochloride

4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester was treated with 3N HCl ethyl acetate (6 mL) andwarmed to reflux for 2 hours, then concentrated, dissolved in a minimumof methanol which was saturated with Et₂O and stirred 18 hours. Theproduct was collected by filtration (49 mg, 73%). ¹H NMR (400 MHz,DMSO-d₆) δ 9.66 (br s, NH), 7.86 (br s, NH), 7.74–7.70 (m, 2H), 7.49 (d,J=7.5 Hz, 1H), 3.33–2.97 (m, 6H), 2.17 (m, 1H), 2.01 (d, J=11.0 Hz, 1H).GCMS m/e 184 (M⁺). M.p. 268–273° C.

EXAMPLE 333-(10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL)-5-METHYL-1,2,4-OXADIAZOLE HYDROCHLORIDE

4-Cyano-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (300 mg, 1.1 mmol) was stirred in ethanol (10 mL).To this hydroxyl amine hydrochloride (382 mg, 5.5 mmol) and NaOH (242mg, 6.05 mmol) were added and the mixture was warmed to reflux. After 45minutes, the reaction was cooled, diluted with H₂O and extracted withethyl acetate. The organic layer was dried (Na₂SO₄) and concentrated toafford a yellow solid (110 mg, 0.35 mmol). This solid was dissolved inpyridine (1 mL) and treated with acetyl chloride (0.03 mL, 0.415 mmol)and warmed to 100° C. for 18 hours. The reaction was cooled, treatedwith H₂O and extracted with ethyl acetate. The organic extracts werewashed with water and saturated aqueous NaCl solution, dried (Na₂SO₄)and concentrated. Chromatography on Silica gel afforded product (50 mg,0.15 mmol). (25% ethyl acetate/hexanes R_(f) 0.18). This product wastreated with 2N HCl methanol (10 mL), heated to 70° C. for 1 hour,cooled, concentrated and recrystallized from methanol/Et₂O to provideproduct (15 mg). APCI MS m/e 242.2 [(M+1)⁺].

EXAMPLE 341-(10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-YL)-1-ETHANONEHYDROCHLORIDE A)1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(253 mg, 1.0 mmol) and AcCl (0.68 mL, 10 mmol) were dissolved in DCE (3mL) and treated with aluminum chloride (AlCl₃) (667 mg, 5.0 mmol). Theresulting yellow mixture was stirred for 30 minutes then poured over iceand saturated aqueous NaHCO₃ solution. After stirring 20 minutes themixture was extracted with CH₂Cl₂ (3×30 mL). The organic layer was driedthrough a cotton plug then concentrated to a orange-yellow oil (255 mg,86%).

B)4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester

1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(1.3 g, 4.37 mmol) and 37% aqueous NH₄OH solution (10 mL) were stirredin methanol (30 ml) for 3 hours, then concentrated and azeotroped withmethanol (2×50 mL). (This product could be converted to an HCl saltdirectly: see the next example.) The resulting product was stirred in1,4-dioxane (20 mL) and treated with saturated aqueous Na₂CO₃ solution(5 mL). To this was added di-t-butyldicarbonate (1.91 g, 8.74 mmol).After stirring 2 hours, the reaction was treated with H₂O (50 mL),extracted with CH₂Cl₂ (4×30 mL), dried (Na₂SO₄), filtered, concentratedand chromatographed to provide an oil (1.3 g, 100%). (TLC 40% ethylacetate/hexanes R_(f) 0.56).

C)1-(10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanonehydrochloride

4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester (190 mg, 0.63 mmol) was treated with excess 3N HClethyl acetate and warmed to 70° C. for 1 hour then concentrated anddissolved in a minimum of methanol. The resulting solution was saturatedwith Et₂O and stirred. After 18 hours the white crystalline product wascollected by filtration (81 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.75(br s, NH), 7.89 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.74 (br s, NH), 7.44(d, J=8.0 Hz, 1H), 3.33 (br s, 2H), 3.22 (br s, 2H), 3.00 (br m, 2H),2.54 (s, 3H), 2.17 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). GCMS m/e 201 (M⁺).M.p. 198–202° C.

EXAMPLE 35 10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIEN-4-OLHYDROCHLORIDE A) Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylester

1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(2.5 g, 8.41 mmol) and 3-chloroperoxybenzoic acid (m-CPBA) (7.5 g, 42mmol) were stirred in CH₂Cl₂ (20 mL) and warmed to 40° C. for 18 hours.The mixture was cooled to room temperature, then treated withdimethylsulfide (Me₂S) (3 mL, 40.8 mmol) and stirred 24 hours. Theresulting mixture was poured into ice and saturated aqueous Na₂CO₃solution (100 mL) then extracted with Et₂O (4×40 mL). The organic layerwas washed saturated aqueous Na₂CO₃ solution (3×40 mL) then dried(Na₂SO₄), filtered and concentrated to afford an oil (1.83 g, 69%). (TLCethyl acetate R_(f) 0.80).

B)2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone

Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylester (900 mg, 2.87 mmol) was stirred in methanol (20 mL) and saturatedaqueous NaHCO₃ solution (15 mL) for 48 hours. The mixture wasconcentrated, diluted with H₂O and extracted with CH₂Cl₂ (3×20 mL) thendried through a cotton plug. Chromatography on Silica gel provided pureproduct (420 mg, 54%). (TLC 5% methanol/CH₂Cl₂ R_(f) 0.44). ¹H NMR (400MHz, CDCl₃) δ 7.05 (m, 1H), 6.70 (m, 1H), 6.62 (m, 1H), 4.32 (m, 1H),3.84 (m, 1H), 3.48 (m, 1H), 3.21 (br s, 1H), 3.16 (br s, 1H), 3.09 (m,1H), 2.38 (m, 1H), 1.97 (d, J=11.0 Hz, 1H).

C) 10-Azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol hydrochloride

2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(50 mg, 0.184 mmol) was dissolved in methanol/H₂O (3/1, 5 mL), treatedwith Na₂CO₃(s) (40 mg, 0.369 mmol) and warmed to 65° C. for 2 hours. Themixture was concentrated, diluted with H₂O and extracted with CH₂Cl₂(3×20 mL) then dried through a cotton plug. Filtration through a Silicagel plug provided an oil (10% methanol/CH₂Cl₂) which was treated with 3NHCl ethyl acetate (3 mL) then concentrated, dissolved in a minimum ofmethanol which was saturated with Et₂O and stirred. After 18 hours thewhite crystalline product was collected by filtration (10 mg, 26%). ¹HNMR (400 MHz, CDOD₃) δ 7.16 (d, J=8.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H),6.72 (dd, J=8.0,2.0 Hz, 1H), 3.32–3.28 (4H), 3.09 (dd, J=14.5,12.0 Hz,2H), 2.32 (m, 1H), 2.03 (d, J=11.0 Hz, 1H). APCI MS m/e 176.2 [(M+1)⁺].M.p. 308 (dec.)° C.

EXAMPLE 367-METHYL-5-OXA-6,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]PENTADECA-2,4(8),6,9-TETRAENEHYDROCHLORIDE A)1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

Acetic acid10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ylester (800 mg, 2.55 mmol) was combined with AlCl₃ (1.0 g, 7.65 mmol) andwarmed to 170° C. for 2 hours. The mixture was cooled and treated with1N aqueous HCl solution (20 mL), extracted with ethyl acetate and dried(Na₂SO₄). Chromatography affords an oil (190 mg, 24%). (TLC ethylacetate R_(f) 0.75). ¹H NMR (400 MHz, CDCl₃) δ 12.58 (s, 0.5H), 12.52(s, 0.5H), 7.53 (s, 1H), 6.86 (s, 1H), 4.33 (m, 1H), 3.91 (m, 1H), 3.56(m, 1H), 3.28 (br s, 1H), 3.24 (br s, 1H), 3.14 (m, 1H), 2.35 (m, 1H),1.97 (br d, J=11.2 Hz, 1H).

B)2,2,2-Trifluoro-1-[4-hydroxy-5-(1-hydroxyimino-ethyl)-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-10-yl]-ethanone

1-(4-Acetyl-5-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(190 mg, 0.605 mmol), hydroxylamine HCl (99 mg, 1.21 mmol) and sodiumacetate (118 mg, 1.21 mmol) were combined in methanol (4 mL) and H₂O (1mL) and warmed to 65° C. for 18 hours. The mixture was cooled, dilutedwith H₂O and extracted with ethyl acetate which was dried (Na₂SO₄),filtered and concentrated to provide a yellow oil (177 mg, 93%).

C)2,2,2-Trifluoro-7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene-ethanone

The above oil,2,2,2-trifluoro-1-[4-hydroxy-5-(1-hydroxyimino-ethyl)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl]-ethanone(177 mg, 0.54 mmol) was stirred in DCE (3 mL), treated withtriethylamine (0.4 mL, 2.8 mmol) and acetic anhydride (Ac₂O) (0.3 mL,2.8 mmol) then stirred 18 hours. The reaction was treated with H₂O andextracted with ethyl acetate. The extracts were dried (Na₂SO₄), filteredand concentrated to a yellow oil which was dissolved in anhydrous DMF (3mL) and treated with 60% NaH in oil (32 mg, 1.08 mmol). After stirring18 hours, additional 60% NaH in oil was introduced (33 mg) and themixture was stirred 2 hours. The reaction was quenched with H₂O (5 mL)and extracted with 80% ethyl acetate/hexanes (3×30 mL). The organiclayer was washed with H₂O (3×20 mL), dried (Na₂SO₄), filtered andconcentrated and chromatographed to provide an oil (40% ethylacetate/hexanes R_(f) 0.56).

D) 7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraenehydrochloride

Utilizing the methods described in Example 9C,2,2,2-Trifluoro-7-Methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene-ethanonewas converted to the title compound. This was treated with 3N HCl ethylacetate (3 mL), concentrated and dissolved in a minimum of CH₂Cl₂ whichwas saturated with hexanes and stirred. After 18 hours the whitecrystalline product was collected by filtration (18 mg, 13% overall). ¹HNMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.63 (s, 1H), 3.42–2.98 (m, 6H),2.50 (s, 3H), 2.23 (m, 1H), 2.08 (d, J=10.5 Hz, 1H). APCI MS m/e 215.2[(M+1)+]

EXAMPLE 374-(2-METHYL-2H-PYRAZOL-3-YL)-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5TRIENEHYDROCHLORIDE and4-(1-METHYL-1H-PYRAZOL-3-YL)-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

1-(4-Acetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(1.0 g, 3.3 mmol) and dimethylformamide dimethylacetal (DMF-DMA) (4.0 g,33.6 mmol) were warmed to 140° C. for 18 hours. After cooling, acrystalline precipitate was filtered and rinsed with ethyl acetate (690mg, 58%).

The above solid,3-dimethylamino-1-(10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-4-yl)-propenone,(200 mg, 0.56 mmol) was dissolved in ethanol (2 mL) and treated with 5NHCl ethanol (0.1 mL) followed by methyl hydrazine (0.6 mmol). Theresulting mixture was warmed to 70° C. for 4 hours. The mixture wascooled, diluted with water and extracted with ethyl acetate, dried(Na₂SO₄) and concentrated. Chromatography on Silica gel provided a 3/1mixture of regioisomeric products (130 mg, 68%). (TLC 50% ethylacetate/hexanes R_(f) 0.40).

The above oil (130 mg, 0.388 mmol) and Na₂CO₃(s) (82 mg, 0.775 mmol)were stirred in methanol (10 mL) and H₂O (5 mL) for 18 hours. Aftercooling the reaction was diluted with water, extracted with CH₂Cl₂ driedthrough a cotton plug and concentrated. The product was purified bychromatography on Silica gel and concentrated to an oil. The salt wasgenerated with 2N HCl methanol, concentrated and recrystallized frommethanol/ethyl acetate to provide a 3/1 mixture of regioisomericpyrrazoles (85 mg, 58%). (5% methanol/CH₂Cl₂ (NH₃) R_(f) 0.25).TFA-precursor APCI MS m/e 336.2 [(M+1) ⁺].

EXAMPLE 384,5-DICHLORO-10-AZATRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A)1-(4,5-Dichloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

(Based on Campaigne, E.; Thompson, W. J. Org. Chem. 1950, 72, 629.)

1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(539 mg, 2.1 mmol) was stirred in CH₂Cl₂ (5 mL) and treated with ICI₃(s) (982 mg, 4.21 mmol). The resulting orange solution was stirred 0.5hours, poured into saturated aqueous NaHSO₃ solution (25 mL), extractedwith CH₂Cl₂ (3×25 mL), dried through a cotton plug and concentrated toan oil (570 mg, 84%) (TLC 50% ethyl acetate/hexanes R_(f) 0.62).

B) 4,5-dichloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

1-(4,5-Dichloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(570 mg, 1.75 mmol) was stirred in methanol (25 mL) and treated withNa₂CO₃(s) (5 g, 47 mmol) in H₂O (5 mL). The stirred mixture was warmedto 70° C. for 4 hours, concentrated to solids, diluted with H₂O andextracted with ethyl acetate (3×40 mL). The product was extracted into1N aqueous HCl solution (2×40 mL) which was washed with ethyl acetatethen neutralized with saturated aqueous Na₂CO₃ solution to pH˜10.Product was extracted with CH₂Cl₂ (3×40 mL), filtered through a cottonplug and concentrated to an oil (400 mg, 100%).

The oil was dissolved in methanol and treated with 3N HCl ethyl acetate(4 mL) and concentrated, then dissolved in a minimum of methanol andwhich was saturated with Et₂O and stirred 18 hours. The product wascollected by filtration (210 mg, 45%). (TLC 50% ethyl acetate/hexanes(NH₃) R_(f) 0.08). ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (s, 2H), 3.33–2.97(m, 6H), 2.18 (m, 1H), 1.99 (d, J=10.5 Hz, 1H). ¹³C NMR (100MHz,DMSO-d₆) δ 141.02, 130.60, 126.58, 45.54, 40.55, 38.30. GCMS m/e227, 229 (M⁺). M.p. 283–291° C.

EXAMPLE 39N⁴,N⁴-DIMETHYL-10-AZATRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENE-4-SULFONAMIDEHYDROCHLORIDE A)10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride

1-(10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(530 mg, 2.1 mmol) was added to chlorosulfonic acid (2 mL, 30 mmol) andstirred for 5 minutes. The mixture was quenched with ice, extracted withethyl acetate, dried (Na₂SO₄), filtered and concentrated to provide anoil (640 mg, 87%). (TLC 30% ethyl acetate/hexanes R_(f) 0.15).

B)N⁴,N⁴-Dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamidehydrochloride

10-Trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride (320 mg, 0.9 mmol) was stirred in THF (10 mL) and treated with40% Me₂NH/H₂O (1.5 mL). After 10 minutes the mixture was concentratedand chromatographed on Silica gel (TLC 30% ethyl acetate/hexanes R_(f)0.31) to provide an oil (256 mg, 78%). This material was dissolved inmethanol (6 mL) and NH₄OH (2 mL) and stirred 18 hours. The mixture wasconcentrated and azeotroped from methanol (3 times) The resulting oilwas dissolved in methanol and treated with 3N HCl ethyl acetate (4 mL),concentrated, dissolved in a minimum of methanol and which was saturatedwith Et₂O and stirred 18 hours. The product was collected by filtrationas a white powder (163 mg, 59%). (TLC 10% methanol/CH₂Cl₂ (NH₃) R_(f)0.54). ¹H NMR (data, free base) (400 MHz, CDCl₃) δ 7.64 (m, 2H), 7.41(d, J=8.0 Hz, 1H), 3.30 (m, 2H), 3.20 (d, J=12.5 Hz, 2H), 3.07 (dd,J=12.5,2.2 Hz, 2H), 2.69 (s, 6H), 2.45, (m, 1H), 2.00 (d, J=11.0 Hz,1H). ¹³C NMR (100 MHz, CDCl₃) δ 128,43, 124.16, 122,75, 46.67, 46.55,42.11, 39, 44, 37,81. GCMS m/e 266 (M⁺). (data HCl salt) ¹H NMR (400MHz, DMSO-d₆) δ 7.68–7.52 (3H), 3.38 (m, 2H), 3.24 (m, 2H), 3.04(m,-2H), 2.58 (s, 6H), 2.22 (m, 1H), 2.04 (d, J=11.0 Hz, 1H). GCMS m/e266 (M⁺). Anal. Calcd. for C₁₃H₁₈N₂O₂HCl: C, 51.56; H, 6.32; N, 9.25.Found C, 51.36; H,6.09; N,9.09.

EXAMPLE 404-(1-PYRROLIDINYLSULFONYL)-10-AZATRICYCLO[6.3.1.0^(2,7)]-DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

The pyrrolidine analogue was prepared from10-trifluoroacetyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonylchloride (320 mg, 0.9 mmol) as by substituting pyrroline in the couplingstep described in Example 39B. The TFA product was isolated as an oil(314 mg, 89%). Deprotection and conversion to the salt as in Example 39Baffords a white powder (189 mg, 63%). (TLC 10% methanol/CH₂Cl₂ (NH₃)R_(f) 0.60). (TLC 50% ethyl acetate/hexanes R_(f) 0.65). ¹H NMR (400MHz, CDCl₃) δ 7.66 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.37 (d, J=8.0 Hz,1H), 3.30–3.15 (m, 8H), 3.00 (m 2H), 2.39 (m, 1H), 1.98 (d, J=11.5 Hz,1H), 1.72 (m, 4H). ¹³C NMR (100 MHz, CDCl₃) δ 146.91, 144.08, 136.65,127.90, 124.18, 122.36, 50.43, 47.87, 46.80, 46.63, 42.11, 39.63, 25.10.APCI MS m/e 293 [(M+1)⁺]. (data HCl salt) ¹H NMR (400 MHz, DMSO-d₆) δ9.78 (br s, NH), 8.1 (br s, NH), 7.73 (d, J=1.5 Hz,1H), 7.66 (dd,J=8.0,1.5 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 3.39–3.01 (10H), 2.21 (m,1H), 2.04 (d, J=11.0 Hz, 1H), 1.66 (m, 4H). GCMS m/e 292 (M⁺). Anal.Calcd. For C₁₃H₁₈N₂O₂HCl.1/2methanol: C, 54.07; H, 6.47; N, 8.51. FoundC, 53.98; H,6.72; N, 8.12

EXAMPLE 415,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2,4(8),9-TRIEN-6-ONEHYDROCHLORIDE

(The title compound was prepared following the procedures described inQuallich, G. J.; Morrissey, P. M. Synthesis 1993, 51–53, treating4,5-dinitro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-10-carboxylicacid tert-butyl ester as an equivalent to an ortho fluoro phenylmoiety.) ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, NH), 9.88 (br s, NH),7.52 (br s, 1H), 7.15 (s, 1H), 6.79 (s, 1H), 3.41 (d, J=5.0 Hz, 2H),3.35–3.13 (m, 4H), 2.93 (m, 2H), 2.12 (m, 1H), 1.95 (d, J=11.5 Hz, 1H).APCI MS m/e 215.2 [(M+1)⁺].

EXAMPLE 426-OXO-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,9)]-PENTADECA-2(10),3,8-TRIENEHYDROCHLORIDE

(For references, see: Nachman, R. J. J. Het. Chem. 1982, 1545.)2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanone(317 mg, 1.11 mmol) was stirred in THF (10 mL), treated withcarbonyldiimidazole (269 mg, 1.66 mmol) and warmed to 60° C. for 18hours. The mixture was concentrated, diluted with CH₂Cl₂ (50 mL) andwashed with 1N aqueous HCl solution (3×10 mL). The organic layer wasdried through a cotton plug, concentrated and chromatographed on Silicagel (50% ethyl acetate/Hexanes) to provide an oil (130 mg). Thismaterial converted to the title compound by the methods described inExample 9C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.78 (s, NH), 9.56 (br s, NH),7.63 (br s, NH), 7.24 (s, 1H), 7.07 (s, 1H), 3.26 (br s, 2H), 3.16 (brt, J=9.5 Hz, 1H), 2.93 (br s, 1H), 2.18 (m, 1H), 1.97 (d, J=11.0 Hz,1H). APCI MS m/e 217.2 [(M+1)⁺].

EXAMPLE 436-BENZYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand phenyl-acetyl chloride were converted to the title compoundfollowing the procedures described in Example 47. ¹H NMR (400 MHz,CD₃OD) δ 7.63 (s, 1H), 7.58 (s, 1H), 7.36–7.24 (5H), 4.29 (s, 2H), 3.46(d, J=2.5 Hz, 2H), 3.39 (d, J=12.0 Hz, 2H), 3.18 (2H), 2.42 (m, 1H),2.15 (d, J=11.5 Hz, 1H). APCI MS m/e 291.2 [(M+1)⁺].

EXAMPLE 44 3-PHENYL-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A) 5-Fluoro-1,4-dihydro-1,4-methano-naphthalene and5-iodo-1,4-dihydro-1,4-methano-naphthalene

(Eisch, J. J.; Burlinson, N. E. J. Amer. Chem. Soc. 1976, 98, 753–761.Paquette, L. A.; Cottrell, D. M.; Snow, R. A. J. Amer. Chem. Soc. 1977,99, 3723–3733.)

Magnesium turnings (9.37 g, 385 mmol) were stirred in anhydrous THF(1000 mL) in a flame dried 2L 3 neck round bottom flask equipped with anon-equalizing addition funnel with a N₂ flow adapter, magnetic stirrerand efficient condenser equipped with a N₂ flow adapter. The flask wasstirred and warmed to reflux by a removable heating mantle.2,6-Difluoro-iodobenzene (0.3 g) was added followed by of 3N EtMgBr inTHF (0.3 mL). The addition funnel was charged with an intimate mixtureof cyclopentadiene (24.24 g, 367 mmol) and 2,6-difluoro-iodobenzene(88.0 g, 367 mmol). Small portions (˜1 mL) of the intimate mixture wereintroduced to assist initiation (˜4 times). After ˜15 minutes, thereaction initiated (exotherm, and vapor condensation) and heating wasmaintained as necessary during the addition of the contents of theaddition funnel. The reaction was then maintained at reflux for ˜1 hour(no SM by GCMS).

The reaction was cooled to room temperature and quenched with H₂O (200mL) followed by aqueous 1N HCl solution (200 mL) to dissolve the solids.Product was extracted with hexanes (4×150 mL). The combined organiclayer was washed with saturated aqueous NaHCO₃ solution (150 mL), dried(Na₂SO₄), filtered through a Silica plug with hexanes rinse andconcentrated to an oil (70 g). Chromatography on Silica gel eluting withhexanes provided two lots (9.0 and 21.0 g), which contained primarily5-iodo-1,4-dihydro-1,4-methano-naphthalene. (TLC hexanes R_(f) 0.63).

B) 5-Iodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol

5-Iodo-1,4-dihydro-1,4-methano-naphthalene (20 g) and N-methylmorpholine N-oxide (17.61 g, 130 mmol) were stirred in acetone (90 mL)and H₂O (13 mL). To this was added a solution of OsO₄ (0.2 mL, 2.5% wt.solution in t-butanol, 0.02 mmol). After 144 hours, Florisil (5 g) andsaturated aqueous NaHSO₃ solution (3 mL) were added and stirred for ½hour. The mixture was filtered through a Celite pad and the filtrateconcentrated to produce an oil which was purified by chromatography onSilica gel eluting with a gradient of hexanes to 100% ethyl acetate toprovide a yellow solid (13.73 g). APCI MS m/e 301.1 [(M−1)⁺].

C) 10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

5-Iodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (8.33 g, 27.6mmol) and Et₃NBnCl (10 mg) were vigorously stirred in dichloroethane (25mL) and H₂O (75 mL) then treated with sodium periodate (6.17 g, 29.0mmol). After 1.5 hours, the layers were separated and the aqueous layerextracted with DCE (2×40 mL). The combined organic layer was washed withH₂O-(4×30 mL) until no reaction to starch iodide paper was observed,then with saturated aqueous NaCl solution (30 mL). The organic layer wasdried through a cotton plug and treated with benzyl amine (3.16 mL, 29.0mmol) and stirred for 2 minutes then transferred to an addition funnel.This solution was added over ˜10 minutes to a vigorously stirred cooled(0° C.) mixture of NaHB(OAc)₃ (18.72 g, 88.0 mmol) in DCE (150 mL).After addition was complete, the mixture was stirred without cooling for2 hours. The mixture was quenched with saturated aqueous Na₂CO₃ solution(100 mL) and stirred for 1 hour, then the layers were separated and theaqueous layer was extracted with CH₂Cl₂ (3×50 mL). The combined organiclayer was washed with saturated aqueous NaCl solution (50 mL), driedthrough a cotton plug and concentrated. Chromatography on Silica gelprovided an oil (6.3 g, 61%). (TLC 5% ethyl acetate/hexanes R_(f) 0.10).¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J=8.0 Hz, 1H), 7.28–7.22 (m, 3H),7.13 (d, J=8.0 Hz,1H), 6.98–6.94 (m, 3H), 3.58 (AB dd, J=14.2 Hz, 2H),3.26 (br s, 1H), 3.21 (br s, 1H), 3.04 (br d, J=10.2 Hz, 1H), 2.83 (brd, J=10.2 Hz, 1H), 2.47 (d, J=10.0 Hz, 1H), 2.39 (d, J=10.0 Hz, 1H),2.34 (m, 1H), 1.72 (d, J=10.5 Hz, 1H). APCI MS m/e 376.0 [(M+1)⁺].

D)10-Benzyl-3-phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

(For a discussion, see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,2457–2483.)10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(375.3 mg, 1.0 mmol), potassium acetate (785 mg, 8.0 mmol) and phenylboronic acid (183 mg, 1.5 mmol) were combined in 10/1 ethanol/H₂O (5mL). The mixture was degassed (3 vacuum/N₂ cycles), treated withtetrakis(triphenylphosphine)palladium(0) (57.5 mg, 0.05 mmol) and warmedto 90° C. for 18 h. The reaction was cooled, diluted with H₂O andextracted with Et₂O (3×50 mL). The organic layer was washed with brine(50 mL), dried (MgSO₄), filtered and concentrated to provide an oil (180mg, 55%). (TLC 4% ethyl acetate/hexanes R_(f) 0.18). GCMS m/e 325 (M)⁺.

E) 3-Phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

10-Benzyl-3-phenyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienewas converted into the title compound utilizing the conditions describedin Example 2D. (TLC 10% methanol/CH₂Cl₂ (NH₃) R_(f) 0.30). (data forfree base) ¹H NMR (400 MHz, CDCl₃) δ 7.46–7.15 (8H), 3.17 (br s, 1H),3.01 (m, 2H), 2.93 (d, J=13.0 Hz, 1H), 2.72 (dd, J=10.5,2.5 Hz, 1H),2.63 (dd, J=10.5,2.5 Hz, 1H), 2.41 (m, 1H), 1.91 (d, J=10.5 Hz, 1H).APCI MS m/e 236.2 [(M+1)⁺]. (HCl salt) M.p. 262–265° C. Anal. Calcd. forC₁₇H₁₇N.HCl.1/3H₂O: C, 73.26; H, 6.86; N, 5.19. Found C, 73.50; H, 6.77;N, 5.04.

EXAMPLE 453-HYDROXY-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE A) 10-Benzyl-3-boronicacid-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

10-Benzyl-3-iodo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(3.0 g, 7.99 mmol) was stirred in anhydrous THF (40 mL) at −78° C. undernitrogen and treated dropwise with n-BuLi (3.84 mL of 2.5M solution inhexanes, 9.59 mmol). After 10 minutes, tri-isopropylborate (4.61 mL,20.0 mmol) was added dropwise. After ˜½ hour, the reaction was pouredinto saturated aqueous NaHCO₃ solution, stirred 5 minutes and extractedwith ethyl acetate (3×50 mL) and concentrated. The residue was dissolvedin 30% Et₂O/hexanes and extracted with 1N NaOH aqueous solution (4×50mL). The combined aqueous basic layer was treated with concentrated HClto achieve pH 8 and extracted with ethyl acetate (4×25 mL), dried(Na₂SO₄) and stripped. Chromatography on Silica gel eluting first with3% ethyl acetate/hexanes to remove non-polar components, then with 5%methanol/CH₂Cl₂ provides the title compound. (TLC 25% ethylacetate/hexanes R_(f) 0.60).

B)10-Benzyl-3-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

10-Benzyl-3-boronicacid-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (140 mg, 0.48mmol) dissolved in THF (5 mL) was treated withN-methylmorpholine-N-oxide (64.5 mg, 0.48 mmol) and brought to refluxfor 1 hour. The reaction was concentrated and chromatographed on Silicagel to provide product. (TLC 25% ethyl acetate/hexanes R_(f) 0.18). ¹HNMR (400 MHz, CDCl₃) δ 7.18–7.15 (3H), 7.04 (dd, J=8.0,7.0 Hz, 1H), 6.95(m, 2H), 6.75 (d, J=7.0 Hz, 1H), 6.59 (dd, J=8.0,1.0 Hz, 1H), 3.53 (brs, OH), 3.51 (AB d, J=14.0 Hz, 2H), 3.28 (br s, 1H), 3.06 (br s, 1H),2.91 (dd, J=8.5,1.5 Hz, 1H), 2.79 (ddd, J=8.5,1.5,1.5 Hz, 1H), 2.42 (d,J=11.0 Hz, 1H), 2.39 (d, J=11.0 Hz, 1H), 2.23 (m, 1H), 1.65 (d, J=10.5Hz, 1H). APCI MS m/e 266.5 [(M+1)⁺].

C) 3-Hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trienehydrochloride

10-Benzyl-3-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene(160 mg, 0.60 mmol) was converted into the title compound by the methodsdescribed in Example 1D. ¹H NMR (400 MHz, CDCl₃) δ 7.15 (dd, J=8.0,7.5Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 3.51 (br s,1H), 3.33–3.25 (3H), 3.16 (d, J=12.0 Hz, 1H), 3.09 (d, J=12.0 Hz, 1H),2.29 (m, 1H), 2.02 (d, J=11.0 Hz, 1H). APCI MS m/e 175.8 [(M+1)⁺]. (HClsalt) M.p. 253–255° C.

EXAMPLE 464,5-DIFLUORO-10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENEHYDROCHLORIDE

The title compound was prepared by the methods described in Examples 1and 2 starting with 2,4,5-trifluorobromobenzene. ¹H NMR (400 MHz, CDCl₃)δ 7.31 (t, J=8.5 Hz, 2H), 3.48–3.13 (6H), 2.38 (m, 1H), 2.11 (d, J=11.5Hz, 1H). APCI MS m/e 196.2 [(M+1)⁺]. (HCl salt) M.p. 301–303° C. Anal.Calcd. for C₁₁H₁₁F₂N.HCl.1/6H₂O: C, 56.30; H, 5.30; N, 5.97. Found C,56.66; H, 5.41; N, 5.96.

EXAMPLE 476-ETHYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand propionyl chloride were converted to the title compound followingthe procedures described in Example 30 and Goldstein, S. W.; Dambek, P.J. J. Het. Chem. 1990, 27, 335. ¹H NMR (400 MHz, CD₃OD) δ 7.64 (s, 1H),7.62 (s, 1H), 3.48 (d, J=2.5 Hz, 2H), 3.41 (d, J=12.0 Hz, 2H), 3.20(2H), 3.01 (q, J=7.5 Hz, 2H), 2.45 (m, 1H), 2.17 (d, J=11.5 Hz, 1H),1.42 (t, J=7.5 Hz, 3H). APCI MS m/e 229.2 [(M+1)⁺].

EXAMPLE 486-ISOPROPYL-5-OXA-7,13-DIAZATETRACYCLO[9.3.1.0^(2,10).0^(4,8)]-PENTADECA-2(10),3,6,8-TETRAENEHYDROCHLORIDE

2,2,2-Trifluoro-1-(4-hydroxy-5-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-ethanoneand isobutyryl chloride were converted to the title compound followingthe procedures described in Example 47. (TLC 25% ethyl acetate/hexanesR_(f) 0.14). ¹H NMR (400 MHz, CD₃OD) δ 7.65 (2H), 3.49 (br s, 2H), 3.41(d, J=12.0 Hz, 2H), 3.33–3.19 (3H), 2.45 (m, 1H), 2.18 (d, J=11.5 Hz,1H), 1.45 (d, J=7.0 Hz, 6H). APCI MS m/e 243.2 [(M+1)⁺]. (HCl salt) M.p.249–251° C.

EXAMPLE 495,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

(Based on the method of Campbell, K. N.; Schaffner, I. J. J. Am. Chem.Soc. 1945, 67, 86.)

1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(607 mg, 1.98 mmol) was dissolved in 95% ethanol/H₂O (5 mL) and treatedwith FeCl₃.6H₂O (800 mg, 2.97 mmol), ZnCl₂ (27 mg, 0.20 mmol) in ethanol(2 mL). The mixture was warmed to 65° C. for 15 min., treated withacrolein (0.2 mL, 2.97 mmol) and warmed to reflux for 2.5 hours. Themixture was judged complete by TLC, cooled and quenched into saturatedaqueous NaHCO₃ solution (40 mL). The mixture (pH 8.5) was extracted withCH₂Cl₂ (8×30 mL). The organic layer was washed with H₂O and saturatedaqueous NaCl solution then dried through a cotton plug. Concentrationafforded a dark oil which was chromatographed on Silica gel to provide ayellow oil (105 mg, 17%). (TLC 50% ethyl acetate/hexanes R_(f) 0.08).

B)5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(94.7 mg, 0.31 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (36.9 mg). ¹H NMR(400 MHz, CD₃OD) δ 9.19 (m, 2H), 8.33 (s, 1H), 8.27 (s, 1H), 8.10 (dd,J=8.3, 5.6 Hz, 1H), 3.78 (br s, 1H), 3.74 (br s, 1H), 3.58 (br d, J=11.4Hz, 2H), 3.40 (M, 2H), 2.50 (m, 1H), 2.34 (d, J=11.6 Hz, 1H). APCI MSm/e 210.9 [(M+1)⁺]; M.p. 260° C. (dec.); Anal. Calcd. for C₁₄H₁₄N₂.2HCl:C, 59.38; H, 5.69; N, 9.89. Found C, 59.69; H, 5.82; N, 9.79.

EXAMPLE 506-METHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-((6-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7))dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686 mg, 2.00 mmol) was reacted with (E)-2-butenal (0.2 mL, 2.97 mmol)to provide a yellow oil. (335.6 mg, 52%). (TLC 75% ethyl acetate/hexanesR_(f) 0.25).

B)6-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(6-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(308 mg, 0.96 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (186 mg). ¹H NMR(400 MHz, CD₃OD) δ 9.00 (d, J=8.5 Hz, 1H), 8.25 (s, 1H), 8.17 (s, 1H),7.94 (d, J=8.5 Hz, 1H), 3.76 (br s, 1H), 3.71 (br s, 1H), 3.57 (br d,J=11.8 Hz, 2H), 3.38 (M, 2H), 3.01 (s, 3H), 2.49 (m, 1H), 2.32 (d,J=11.6 Hz, 1H). APCI MS m/e 225.2 [(M+1)⁺]; M.p.>300° C. (dec.); Anal.Calcd. for C₁₅H₁₆N₂.2HCl.1/2H₂O: C, 58.83; H, 6.25; N, 9.15. Found C,58.49; H, 6.22; N, 9.02.

EXAMPLE 517-METHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686 mg, 2.00 mmol) was reacted with 2-methylpropenal (0.25 mL, 3.00mmol) to provide a yellow oil (94 mg, 15%). (TLC 10% methanol/CH₂Cl₂R_(f) 0.16).

B)7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(7-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(86 mg, 0.27 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (12.6 mg). ¹H NMR(400 MHz, CD₃OD) δ 9.10 (s, 1H), 9.00 (s, 1H), 8.22 (s, 1H), 8.20 (s,1H), 3.76 (br s, 1H), 3.72 (br s, 1H), 3.57 (br d, J=11.5 Hz, 2H), 3.39(M, 2H), 2.71 (s, 3H), 2.48 (m, 1H), 2.32 (d, J=11.6 Hz, 1H). APCI MSm/e 225.0 [(M+1)⁺].

EXAMPLE 527-ETHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(686 mg, 2.00 mmol) was reacted with 2-ethylpropenal (0.35 mL, 3.60mmol) to provide a yellow oil (110 mg, 16%). (TLC 75% ethylacetate/hexanes R_(f) 0.32).

B)7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(7-Ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(94 mg, 0.28 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (33 mg). ¹H NMR(400 MHz, CD₃OD) δ 9.12 (s, 1H), 9.00 (s, 1H), 8.23 (s, 1H), 8.18 (s,1H), 3.76 (br s, 1H), 3.72 (br s, 1H), 3.56 (br d, J=11.5 Hz, 2H), 3.37(M, 2H), 3.05 (q, J=7.5 Hz, 2H), 2.48 (m, 1H), 2.32 (d, J=11.6 Hz, 1H),1.44 (t, J=7.5 Hz, 3H). APCI MS m/e 239.1 [(M+1)⁺]; M.p. 288–291° C.(dec.); Anal. Calcd. for C₁₆H₁₈N₂.2HCl.H₂O: C, 58.36; H, 6.73; N, 8.51.Found C, 57.98; H, 5.99; N, 8.41.

EXAMPLE 538-METHYL-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

Following the method described in Example 49A,1-(4-Amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(775 mg, 2.52 mmol) was reacted with 1-buten-3-one (0.32 mL, 3.79 mmol)to provide a yellow oil. (424 mg, 52%). (TLC 50% ethyl acetate/hexanesR_(f) 0.08).

B)8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(8-Methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(403 mg, 1.26 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide a crystalline solid (266 mg). ¹H NMR(400 MHz, CD₃OD) δ 9.01 (d, J=5.6 Hz, 1H), 8.49 (s, 1H), 8.22 (s, 1H),7.97 (d, J=5.6 Hz, 1H), 3.76 (br m, 2H), 3.58 (br d, J=11.5 Hz, 2H),3.40 (m, 2H), 3.06 (s, 3H), 2.48 (m, 1H), 2.33 (d, J=11.6 Hz, 1H). Anal.Calcd. for C₁₅H₁₆N₂.2HCl.H₂O: C, 57.15; H, 6.39; N, 8.89. Found C,57.43; H, 6.44; N, 8.82.

EXAMPLE 545,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,7,9-TETRAEN-6-ONEHYDROCHLORIDE A) 3,3-Dimethoxypropanoic acid lithium salt

(Related to methods described in Alabaster, C. T. et. al., J. Med. Chem.1988, 31, 2048–2056.) 3,3-Dimethoxypropanoic acid methyl ester (14.25 g,96.2 mmol) in THF (100 mL) was treated with LiOH.H₂O (2.5 g, 106 mmol)and H₂O (2 mL). The mixture was brought to reflux for 4 hours, cooled toroom temperature and azeotropically dried from THF (4 times) to providewhite solids (13.3 g).

B)1-(4-(N-3′,3′-Dimethoxy-propionamide)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone

3,3-Dimethoxypropanoic acid lithium salt (840 mg, 6.0 mmol) in THF (15mL) was treated with trifluoroacetic anhydride (0.85 mL, 6.0 mmol)dropwise and stirred for 15 minutes. The resulting yellow solution wasadded dropwise to a vigorously stirred mixture of1-(4-amino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(540 mg, 2 mmol) in THF (5 mL) and saturated aqueous NaHCO₃ solution (2mL). After 3 hours the reaction mixture was diluted with H₂O andextracted with ethyl acetate (3 times). The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated to an oil whichwas purified by chromatography on Silica gel to provide a white solid(477 mg, 62%). (TLC 50% ethyl acetate/hexanes R_(f) 0.37).

C)1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone

1-(4-(N-3′,3′-Dimethoxy-propionamide)-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(460 mg, 1.19 mmol) was treated with trifluoroacetic acid (4 mL) andstirred 18 hours, concentrated, diluted with CH₂Cl₂ and H₂O. The aqueouslayer was extracted with CH₂Cl₂ (4 times) and the organic layer waswashed with saturated aqueous NaHCO₃ solution (40 mL) and saturatedaqueous NaCl solution then dried through a cotton plug. Concentrationafforded a yellow solid (320 mg, 83%).

D)5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-onehydrochloride

1-(5,14-Diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone(540 mg, 2 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide the title compound a pink crystallinesolid (72 mg, 71%). ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=8.8 Hz, 1H),7.90 (s, 1H), 7.66 (s, 1H), 6.98 (d, J=8.8 Hz, 1H), 3.59 (br s, 1H),3.56 (br s, 1H), 3.49 (dd, J=12.4, 5.8 Hz, 2H), 3.29 (m, 2H), 2.42 (m,1H), 2.23 (d, J=11.6 Hz, 1H). APCI MS m/e 227 [(M+1)⁺]; M.p. 300° C.(dec.); Anal. Calcd. for C₁₄H₁₄N₂0.2HCl: C, 56.20; H, 5.39; N, 9.36.Found C, 56.40; H, 5.63; N, 9.25.

EXAMPLE 556-CHLORO-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

1-(5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone(156 mg, 0.49 mmol) was treated with POCl₃ (5 mL) and warmed to 100° C.with stirring for 3 hours. After concentration in vacuo, the residue wasdiluted with CH₂Cl₂ (15 mL) and carefully treated with saturated NaHCO₃solution (10 mL) with stirring. Once CO₂ evolution slowed the mixturewas separated and the aqueous layer extracted CH₂Cl₂ (3 times). Theorganic layer was washed with H₂O and saturated NaCl solution, filteredthrough cotton and concentrated to a brown oil (217 mg, 93%). (TLC ethylacetate, R_(f) 0.3) ¹H NMR (400 MHz, ²HCCl₃) δ 8.03 (d, J=8.5 Hz, 1H),7.83 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 4.43 (m, 1H), 4.01(m, 1H), 3.62 (m, 1H), 3.29 (m, 2H), 3.23 (m, 1H), 2.45 (m, 1H), 2.10(d, J=11.6 Hz, 1H). APCI MS m/e 341.1 [(M+1)⁺].

B)6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone(26 mg, 0.076 mmol) was converted to the title compound using methodsdescribed in Example 7 to provide the title compound a solid (5.8 mg,24%). ¹H NMR (free base, 400 MHz, 2HCCl₃) δ 8.01 (d, J=8.5 Hz, 1H), 7.77(s, 1H), 7.57 (s, 1H), 7.30 (d, J=8.5 Hz, 1H), 3.28 (br s, 1H), 3.24 (brs, 1H), 3.12 (br d, J=12.5 Hz, 2H), 2.96 (br d, J=12.5 Hz, 2H), 2.41 (m,1H), 2.02 (d, J=11.6 Hz, 1H). APCI MS m/e 245.1 [(M+1)⁺].

EXAMPLE 56 6-METHOXY-5,14-DIAZATETRACYCLO10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENE HYDROCHLORIDE A)6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester

6-Chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene(2.82 g, 11.53 mmol) was converted into the title compound as describedin Example 12A to provide a brown oil (3.55 g, 89%). (TLC: 5%methanol/CH₂Cl₂, R_(f) 0.37).

B)6-Methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester

Sodium metal (˜12 mg) was dissolved in methanol (1 mL) under nitrogenwith stirring and treated with a solution of6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester (118 mg, 0.33 mmol) in methanol (3 mL) and broughtto reflux for 18 hours. The mixture was cooled, concentrated, treatedwith H₂O and extracted with CH₂Cl₂. The organic layer was washed withsaturated NaCl solution and filtered through a cotton plug thenconcentrated to an oil (165 mg). (TLC: 5% methanol/CH₂Cl₂ R_(f) 0.55).

C)6-Methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

6-Methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylicacid tert-butyl ester (138 mg, 0.41 mmol) was dissolved intrifluoroacetic acid (4 mL) brought to reflux for 4 hours. The mixturewas cooled and concentrated to an oil which was dissolved in ethylacetate and treated with 3N HCl/ethyl acetate (1 mL). Afterconcentration the residue was recrystallized from methanol/diethyl etherto provide a beige solid (51 mg, 26%). ¹H NMR (400 MHz, CD₃OD) δ 8.77(d, J=9.5 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.54 (d, J=9.5 Hz, 1H),4.30 (s, 3H), 3.65 (br s, 1H), 3.61 (br s, 1H), 3.50 (dd, J=12.4, 3.8Hz, 2H), 3.29 (m, 2H), 2.44 (m, 1H), 2.24 (d, J=11.6 Hz, 1H). APCI MSm/e 241.2 [(M+1)⁺]; M.p. 240, (darkens), 275° C. (dec.); (TLC: 10%methanol (NH₃)/CH₂Cl₂, R_(f) 0.38).

EXAMPLE 576-CHLORO-10-FLUORO-5,14-DIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,5,7,9-PENTAENEHYDROCHLORIDE A)1-(6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanone

3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-triene wasconverted to1-(3-Fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]-dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanoneby the methods described in Example 7A. This product was nitrated asdescribed in Example 7B. The resulting mixture of nitrated products wasreduced as described in Example 8, then converted to a chloroquinolineas described in Examples 54 and 55. These products were separated bycolumn chromatography on silica gel to provide the title compound. (TLC:50% ethyl acetate/hexanes, R_(f) 0.50).

B)6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaenehydrochloride

1-(6-Chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaen-10-yl)-2,2,2-trifluoro-ethanonewas converted to 6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene by methods described inExample 7C. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J=8.5, 1.5 Hz, 1H), 7.36(d, J=8.5 Hz, 1H), 7.24 (s, 1H), 3.52 (br s, 1H), 3.16 (br s, 1H), 3.11(dd, J=12.8, 1.6 Hz, 2H), 2.97 (ddd, J=12.8, 2.5, 2.5 Hz, 1H), 2.85(ddd, J=12.8, 2.5, 2.5 Hz, 1H), 2.46 (m, 1H), 2.06 (d, J=10.8 Hz, 1H).El MS m/e 263 [M⁺]. This material was converted to the title compound asdescribed in Example 7C.

EXAMPLE 585,8,14-TRIAZATETRACYCLO[10.3.1.0^(2,11).0^(4,9)]HEXADECA-2(11),3,7,9-TETRAEN-6-ONEHYDROCHLORIDE A)1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-on-10-yl)-2,2,2-trifluoro-ethanone

1-(4,5-Diamino-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone(536 mg, 1.88 mmol) was stirred in ethanol (4 ml). This mixture wastreated with methyl-2-hydroxyl-2-methoxy acetate (0.203 mL, 2.07 mmol)and stirred at 70° C. for 2.5 hours. The reaction was cooled to roomtemperature and concentrated. Trituration with methanol and filtrationprovided light yellow solids (337 mg, 55%). (TLC 10% methanol/CH₂Cl₂R_(f) 0.57).

B)5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-onehydrochloride

1-(5,8,14-Triazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-on-10-yl)-2,2,2-trifluoro-ethanone(145 mg, 0.45 mmol) was converted to the title compound by the methodsdescribed in Example 7C to provide a brown solid (26 mg, 46%). ¹H NMR(400 MHz, D₂O) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.18 (s, 1H), 3.39 (br s,2H), 3.28 (br d, J=12.5 Hz, 1H), 3.12 (br d, J=12.5 Hz, 1H), 2.29 (m,1H), 1.99 (d, J=12.0 Hz, 1H). APCI MS m/e 228.2 [(M+1)⁺]; M.p. 296,(darkens), 310° C. (dec.); (TLC: 10% CH₂Cl₂/methanol(NH₃), R_(f) 0.10).

EXAMPLE 59 10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE TOSYLATEA) 3-N-Benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine

A stream of ozone was bubbled through a solution of 4.00 g ofbenzonorbornadiene (1,4-dihydro-1,4-methanonaphthalene) (28.1 mmol, 1.0equivalent) in 80 mL of methanol at −78° C. Once the solution developeda blue color, ozone generation was stopped after another few minutes andthen oxygen was bubbled through for five minutes to dispel the bluecolor. Then the solution was purged with nitrogen for 20 to 40 minutesto deoxygenate the solution. To the cold solution was added 0.199 g of5% platinum on carbon, 55% wet by weight, (0.0281 mmol, 0.001equivalent). The system was passivated with hydrogen, pressurized to 40psi of hydrogen, and gradually warmed to room temperature. Once theozonide was reduced completely (within 45–60 minutes), an additional0.798 g of 5% platinum on carbon (0.112 mmol, 0.004 equivalent) wasadded to the reaction mixture at 0° C., followed by 3.07 mL ofbenzylamine (28.1 mmol, 1.0 equivalent) and 0.561 mL of 96% formic acid(14.0 mmol, 0.50 equivalent). The system was repressurized to 50 psi ofhydrogen and allowed to warm to room temperature. After 4 hours, thereaction mixture was removed from the reactor and filtered through a padof Celite, washing with 20 mL of methanol. This reaction mixture wasused in the next step (Example 59B), but isolation of the intermediatewas carried out as follows: the filtrate was concentrated in vacuo andpartitioned between 40 mL of methylene chloride and 30 mL of a saturatedaqueous solution of sodium carbonate; the aqueous layer was extractedwith another 30 mL of methylene chloride; the combined organic layerswere dried over anhydrous sodium sulfate and concentrated; the residuewas dissolved in 10 mL of 9:1 hexane/ethyl acetate and passed through aplug of silica gel; and after concentrating the filtrate, the titlecompound was obtained as an oil (3.34 g, 48%): ¹H NMR (400 MHz, CD₃OD):δ 7.22–7.19 (m, 7H), 6.93 (d, J=8.0 Hz, 2H), 3.52 (s, 2H), 3.13–3.11 (m,2H), 2.85 (d, J=9.5 Hz, 2H), 2.47 (d, J=9.5 Hz, 2H), 2.32–2.29 (m, 1H),1.71 (d, J=10.0 Hz, 1H).

B) 2,3,4,5-Tetrahydro-1,5-methano-1H-3-benzazepine tosylate

A pressure reactor was charged with the crude3-N-benzyl-2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine (from Example59A prior to workup) in 100 mL of methanol. To the reaction mixture wasadded 3.74 g of p-toluenesulfonic acid monohydrate (19.7 mmol, 0.7equivalent) and 0.986 g of 20% palladium hydroxide on carbon, 50% wet byweight (0.703 mmol, 0.025 equivalent). The reactor was pressurized to 50psi of hydrogen and heated to 40° C. After heating for 15 hours thereactor was cooled to room temperature. The reaction mixture wasfiltered through Celite, washing with methanol. The filtrate wasconcentrated in vacuo and stripped down from 20 mL of isopropanol. Theresidue was redissolved in 32 mL of isopropanol and heated to 70° C. Tothe hot solution was added 16 mL of hexane and the resulting solutionwas allowed to slowly cool with stirring. Crystals formed and werestirred at room temperature for 12 hours. The white crystals werefiltered and dried to give 2.65 g (28%) of the tosylate salt of2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine tosylate; mp: 207–208°C.; ¹H NMR (400 MHz, CD₃OD): δ 7.69 (d, J=7.9 Hz, 2H), 7.43–7.32 (m,4H), 7.23 (d, J=7.9 Hz, 2H), 3.37 (d, J=11.2 Hz, 4H), 3.30 (bs, 2H),3.15 (d, J=12.4 Hz, 2H), 2.36 (s, 3H), 2.40–2.35 (m, 1H), 2.08 (d,J=11.2 Hz, 1H); ¹³C NMR (100 MHz, CD₃OD): δ 140.8, 140.5, 139.1, 127.2,127.2, 124.3, 122.3, 45.1, 39.7, 37.3, 18.7; IR (KBr, cm⁻¹): 3438, 3021,2958, 2822, 2758, 2719, 2683, 2611, 2424, 1925, 1606, 1497, 1473, 1428,1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945,914, 876, 847, 829, 818, 801, 710, 492; Anal. Calcd for C₁₈H₂₁NO₃S: C,65.23; H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N, 4.26.

EXAMPLE 60 10-AZA-TRICYCLO[6.3.1.0^(2,7)]DODECA-2(7),3,5-TRIENE TOSYLATEA) 3-Oxo-indan-1-carboxylic acid methyl ester

A solution of 10.0 g of 3-oxo-indan-1-carboxylic acid (56.8 mmol, 1.0equivalent) and 0.25 mL of concentrated sulfuric acid in 20 mL ofmethanol was heated to a reflux for 4 hours. The reaction mixture wasthen cooled to room temperature and diluted with 100 mL ofmethyl-tert-butyl alcohol. The organic solution was washed twice with 60mL of a saturated aqueous sodium bicarbonate solution, and once with 50mL of a saturated aqueous sodium chloride solution. The organic layerwas dried over anhydrous sodium sulfate and concentrated. The titlecompound crystallized as a white solid upon concentration, (10.4 g,96%); mp: 46–47° C.; ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, J=7.6 Hz, 1H),7.68 (d, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 1H),4.29 (dd, J=8.0, 3.4 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J=19.1, 3.4 Hz,1H), 2.86 (dd, J=19.1, 8.0 Hz, 1H); ¹³C NMR (100 MHz, CD₃OD): δ 204.4,172.5, 151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR(neat, cm⁻¹): 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206,1168, 1092, 1044, 1014,986, 881, 837, 760, 686, 580, 538.

B) 3-Cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester

To a solution of 3.80 g of 3-oxo-indan-1-carboxylic acid methyl ester(20.0 mmol, 1 equivalent) in 6 mL of toluene and 2 mL of acetonitrilewas added 192 mg of zinc iodide (0.600 mmol, 0.03 equivalent) followedby 3.47 mL of trimethylsilyl cyanide (26.0 mmol, 1.3 equivalent). Thereaction mixture was heated to 50° C. for 5 hours. The reaction mixturewas then cooled to room temperature and diluted with 12 mL of tolueneand 8 mL of a saturated aqueous sodium bicarbonate solution. Afterstirring the mixture for 1 hour the layers were separated. The organiclayer was washed with another 8 mL of a saturated aqueous sodiumbicarbonate solution followed by 8 mL of a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous sodiumsulfate and concentrated in vacuo to give3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester as anoil (5.61 g, 97%). The silylated cyanohydrin title compound was obtainedas a mixture of two diastereomers in a 2:1 ratio: ¹H NMR (400 MHz,CDCl₃): (major isomer) δ 7.54–7.50 (m, 1H), 7.42–7.38 (m, 3H), 4.14 (t,J=7.7 Hz, 1H), 3.78 (s, 3H), 3.01 (dd, J=13.3, 7.5 Hz, 1H), 2.79 (dd,J=13.3, 7.5 Hz, 1H), 0.26 (s, 9H); (minor isomer) 67.59–7.55 (m, 1H),7.48–7.44 (m, 3H), 4.29 (t, J=7.5 Hz, 1H), 3.78 (s, 3H), 3.03 (dd,J=13.7, 7.5 Hz, 1H), 2.70 (dd, J=13.7, 7.5 Hz, 1H), 0.14 (s, 9H); ¹³CNMR (100 MHz, CDCl₃): (unassigned) δ 172.3, 172.0, 142.3, 142.1, 140.1,138.8, 130.8, 130.5, 129.1, 128.9, 125.8, 125.6, 124.7, 124.3, 120.8,120.6, 75.4, 75.3, 52.7, 52.7, 47.4, 46.8, 45.6, 45.3, 1.4, 1.3; IR(neat, cm⁻¹): 2956, 1739, 1477, 1436, 1253, 1197, 1169, 1135, 1092,1033, 1011, 880, 843, 756, 623; Anal. Calcd for C₁₅H1₁₉NO₃Si: C, 62.25;H, 6.62; N, 4.84; Found: C, 62.20; H, 6.53; N, 4.92.

C) 3-Aminomethyl-indan-1-carboxylic acid methyl ester

To a solution of 5.79 g of3-cyano-3-trimethylsilanyloxy-indan-1-carboxylic acid methyl ester (20.0mmol, 1.0 equivalent) in 25 mL of methanol was added 5.71 g ofp-toluenesulfonic acid monohydrate (30.0 mmol, 1.5 equivalent). Thesolution was stirred for 15 minutes and then 4.21 g of 20% palladiumhydroxide on carbon, 50% wet by weight, (3.00 mmol, 0.15 equivalent) wasadded. The reaction mixture was subjected to hydrogenolysis at 50 psi ofhydrogen over 24 hours. After this time, the reaction mixture wasfiltered through Celite and typically used-filtrate in the next step(Example 60D). The isolation of the title compound was conducted asfollows: the filtrate was concentrated in vacuo; the residue waspartitioned between 30 mL of methylene chloride and 20 mL of a saturatedaqueous solution of sodium carbonate; the aqueous layer was extractedwith 15 mL of methylene chloride; the combined aqueous layers werewashed with 40 mL of a saturated aqueous solution of sodium chloride;the organic solution was dried over anhydrous sodium sulfate andconcentrated to afford the title compound as an oil (3.65 g, 89%) withapproximately a 10:1 ratio of diastereomers; (major diastereomer) ¹H NMR(400 MHz, CDCl₃): δ 7.43 (dd, J=6.9, 1.6 Hz, 1H), 7.29–7.25 (m, 3H),4.09 (t, J=8.1 Hz, 1H), 3.80 (s, 3H), 3.31–3.24 (m, 1H), 3.14 (dd,J=12.8, 4.7 Hz, 1H), 2.98 (dd, J=12.8, 7.3 Hz,1H), 2.62–2.52 (m, 1H),2.31–2.42 (m, 1H), 1.3 (bs, 2H).

D) 9-Oxo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene

To a solution of 3-aminomethyl-indan-1-carboxylic acid methyl ester(assume 20.0 mmol, 1 equivalent) in 50 mL of methanol (this was thecrude reaction mixture from the prior step, Example 60C) was added 3.84g of sodium tert-butoxide (40.0 mmol, 2.0 equivalent). The reactionmixture was heated to a reflux for 2 hours. The reaction was cooled toroom temperature and concentrated in vacuo. The residue was partitionedbetween 60 mL of ethyl acetate and 40 mL of 5% aqueous solution ofsodium bicarbonate. The aqueous layer was extracted twice more with 50mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated to provide a solid material.Recrystallization of the solid from 10 mL of toluene provided whitecrystals of the title compound (1.78 g, 51%). mp=172–173° C.;. ¹H NMR(400 MHz, CDCl₃): δ 7.33 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22(t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 5.62 (s, 1H), 3.68 (dd,J=11.2, 4.1 Hz, 1H), 3.55 (d, J=3.7 Hz, 1H), 3.43–3.37 (m, 1H), 3.18 (d,J=11.2 Hz, 1H), 2.52–2.45 (m, 1H), 2.32 (d, J=11.2 Hz, 1H); ¹³C NMR (100MHz, CDCl₃): δ 173.6, 144.7, 144.6, 128.0, 127.7, 123.2, 122.9, 49.3,47.9, 39.1, 38.4; IR (neat, cm⁻¹): 3218, 2949, 2872, 1666, 1485, 1459,1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104, 1045, 1004, 946, 910,756, 730, 643, 613; Anal. Calcd for C₁₁H1₂₁NO: C, 76.28; H, 6.40; N,8.09; Found: C, 75.94; H, 6.27; N, 7.99.

E) 10-Aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene tosylate

To a solution of 1.38 g of9-oxo-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene (8.00 mmol, 1equivalent) in 8 mL of tetrahydrofuran was added 603 mg of sodiumborohydride (16.0 mmol, 2.0 equivalent) followed by slow addition of2.77 mL of boron trifluoride diethyl etherate (21.6 mmol, 2.7equivalent). Once the effervescence subsided, the reaction mixture washeated to 50° C. for 5 hours. The reaction was then cooled to roomtemperature for addition of 10 mL of methanol (added dropwise at first)and 0.125 mL of concentrated hydrochloric acid. Heating was resumed at areflux for 12 hours. The reaction mixture was then cooled to roomtemperature and concentrated in vacuo. The residue was diluted with 20mL of 20% aqueous sodium hydroxide followed by 30 mL ofmethyl-tert-butyl ether. The mixture was stirred for 30 minutes and thenthe aqueous layer was extracted with another 30 mL of methyl-tert-butylether. The combined organic layers were washed with 40 mL of a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. After concentrating in vacuo, 1.67 g of p-toluenesulfonic acidmonohydrate (8.80 mmol, 1.1 equivalent) was added with 20 mL ofisopropanol. The solution was heated until homogeneous and then allowedto gradually cool to room temperature with stirring. White crystals ofthe title compound formed and were collected by filtration (2.17 g,81%). mp: 207–208° C.; ¹H NMR (400 MHz, CD₃OD): δ 7.69 (d, J=7.9 Hz,2H), 7.43–7.32 (m, 4H), 7.23 (d, J=7.9 Hz, 2H), 3.37 (d, J=11.2 Hz, 4H),3.30 (bs, 2H), 3.15 (d, J=12.4 Hz, 2H), 2.36 (s, 3H), 2.40–2.35 (m, 1H),2.08 (d, J=11.2 Hz, 1H); ¹³C NMR (100 MHz, CD₃OD): δ 140.8, 140.5,139.1, 127.2, 127.2, 124.3, 122.3, 45.1, 39.7, 37.3, 18.7; IR (KBr,cm⁻¹): 3438, 3021, 2958, 2822, 2758, 2719, 2683, 2611, 2424, 1925, 1606,1497, 1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122,1087, 1078, 945, 914, 876, 847, 829, 818, 801, 710, 492; Anal. Calcd forC₁₈H₂₁NO₃S: C, 65.23; H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N,4.26.

1. A compound selected from the group consisting of:(+)-5,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),9-trien-6-one;(+)-6-oxo-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(+)-2-fluoro-N-(4-hydroxy-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-5-yl)-benzamide;(+)-6-methyl-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(+)-5-oxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(+)-7-dimethylamino-5-thia-5-dioxo-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(+)-5-oxa-7-methyl-6-oxo-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,8-triene;(+)-1-(10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl)-1-ethanone;(+)-6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(+)-6-methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-7-methyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-6,7-dimethyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-7-propyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-7-butyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-6-methyl-7-isobutyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-6-methyl-7-phenyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-6-methyl-7-neopentyl-5,7,13-triazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,5,8-tetraene;(+)-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(+)-6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2(10),3,6,8-tetraene;(+)-7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.0^(2,10).0^(4,8)]pentadeca-2,4(8),6,9-tetraene;and pharmaceutically acceptable salts thereof.
 2. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding In thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 1 that is effective in reducingnicotine addiction or aiding In the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 3. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 1 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 4. Amethod for treating a disorder or condition selected from inflammatorybowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn'sdisease, irritable bowel syndrome, spastic dystonia, chronic pain, acutepain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension,bulimia, anorexia, obesity, cardiac arrythmias, gastric acidhypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies on, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 1 thatis effective in treating such disorder or condition.
 5. A method fortreating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 1 that is effective in attention deficithyperactivity disorder.
 6. A method for treating Tourette's Syndrome ina mammal, comprising administering to said mammal an amount of acompound according to claim 1 that is effective in treating Tourette'sSyndrome.
 7. A compound selected from the group consisting of:(+)-4-methyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-4-nitro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-4-amino-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-N¹-[10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl]acetamide;(+)-4-chloro-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-3-(10-azatricyclo[6.3.1.0.^(2,7)]dodeca-2(7),3,5-trien-4-yl)-5-methyl-1,2,4-oxadiazole;(+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-ol;(+)-N⁴,N⁴-dimethyl-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-sulfonamide;(+)-4-(1-pyrrolidinylsulfonyl)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(+)-4-ethynyl-5-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-5-ethynyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(+)-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(+)-4-ethynyl-5-chloro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-4-fluoro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-4-chloro-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene-4-carbonitrile;(+)-4-ethynyl-5-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;and pharmaceutically acceptable salts thereof.
 8. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 7 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 9. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 7 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 10. Amethod for treating a disorder or condition selected from inflammatorybowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn'sdisease, irritable bowel syndrome, spastic dystonia, chronic pain, acutepain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension,bulimia, anorexia, obesity, cardiac arrythmias, gastric acidhypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies on, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 7 thatis effective in treating such disorder or condition.
 11. A method fortreating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 7 that is effective in attention deficithyperactivity disorder.
 12. A method for treating Tourette's Syndrome ina mammal, comprising administering to said mammal an amount of acompound according to claim 7 that is effective in treating Tourette'sSyndrome.
 13. A compound selected from the group consisting of:(+)-3-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-4-trifluoromethyl-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-3-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene;(+)-10-azatricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-trien-4-yl cyanide;(+)-4-fluoro-10-aza-tricyclo[6.3.1.0^(2,7)]dodeca-2(7),3,5-triene; andpharmaceutically acceptable salts thereof.
 14. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 13 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 15. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 13 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 16. Amethod for treating a disorder or condition selected from inflammatorybowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn'sdisease, irritable bowel syndrome, spastic dystonia, chronic pain, acutepain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension,bulimia, anorexia, obesity, cardiac arrythmias, gastric acidhypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies on, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 13that is effective in treating such disorder or condition.
 17. A methodfor treating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 13 that is effective in attention deficithyperactivity disorder.
 18. A method for treating Tourette's Syndrome ina mammal, comprising administering to said mammal an amount of acompound according to claim 13 that is effective in treating Tourette'sSyndrome.
 19. A compound selected from the group consisting of:(+)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-6-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-7-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-7-ethyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-8-methyl-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,7,9-tetraen-6-one;(+)-6-chloro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-6-methoxy-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-6-chloro-10-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;(+)-6-chloro-3-fluoro-5,14-diazatetracyclo[10.3.1.0^(2,11).0^(4,9)]hexadeca-2(11),3,5,7,9-pentaene;and pharmaceutically acceptable salts thereof.
 20. A pharmaceuticalcomposition for use in reducing nicotine addiction or aiding in thecessation or lessening of tobacco use in a mammal, comprising an amountof a compound according to claim 19 that is effective in reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse and a pharmaceutically acceptable carrier.
 21. A method for reducingnicotine addiction or aiding in the cessation or lessening of tobaccouse in a mammal, comprising administering to said mammal an amount of acompound according to claim 19 that is effective in reducing nicotineaddiction or aiding in the cessation or lessening of tobacco use.
 22. Amethod for treating a disorder or condition selected from inflammatorybowel disease, ulcerative colitis, pyoderma gangrenosum, Crohn'sdisease, irritable bowel syndrome, spastic dystonia, chronic pain, acutepain, celiac sprue, pouchitis, vasoconstriction, anxiety, panicdisorder, depression, bipolar disorder, autism, sleep disorders, jetlag, amyotrophic lateral sclerosis, cognitive dysfunction, hypertension,bulimia, anorexia, obesity, cardiac arrythmias, gastric acidhypersecretion, ulcers, pheochromocytoma, progressive supranuclearpalsy; chemical dependencies and addictions; dependencies on, oraddictions to, nicotine, tobacco products, alcohol, benzodiazepines,barbiturates, opioids or cocaine; headache, migraine, stroke, traumaticbrain injury, obsessive-compulsive disorder, psychosis, Huntington'schorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia,multi-infarct dementia, age-related cognitive decline, epilepsy,including petit mal absence epilepsy, senile dementia of the Alzheimer'stype, Parkinson's disease, attention deficit hyperactivity disorder andTourette's Syndrome in a mammal, comprising administering to a mammal inneed of such treatment an amount of a compound according to claim 19that is effective in treating such disorder or condition.
 23. A methodfor treating attention deficit hyperactivity disorder in a mammal,comprising administering to said mammal an amount of a compoundaccording to claim 19 that is effective in attention deficithyperactivity disorder.
 24. A method for treating Tourette's Syndrome ina mammal, comprising administering to said mammal an amount of acompound according to claim 19 that is effective in treating Tourette'sSyndrome.